The clinical penetrance of infectious diseases varies considerably among patients with inborn errors of immunity (IEI), even for identical genetic defects. This variability is influenced by pathogen exposure, healthcare access and host-environment interactions. We describe here a patient in his thirties who presented with epidermodysplasia verruciformis (EV) due to infection with a weakly virulent beta-papillomavirus (HPV38) and CD4+ T-cell lymphopenia. The patient was born to consanguineous parents living in the United States. Exome sequencing identified a previously unknown biallelic STK4 stop-gain mutation (p.Trp425X). The patient had no relevant history of infectious disease during childhood other than mild wart-like lesion on the skin, but he developed diffuse large B-cell lymphoma (DLBCL) and EBV viremia with a low viral load in his thirties. Despite his low CD4+ T-cell count, the patient had normal counts of CD3+ cells, predominantly double-negative T cells (67.4%), which turned out to be Vδ2+ γδ T cells. γδ T-cell expansion has frequently been observed in the 33 reported cases with STK4 deficiency. The Vδ2 γδ T cells of this STK4-deficient patient are mostly CD45RA-CD27+CCR7+ central memory γδT cells, and their ability to proliferate in response to T-cell activation was impaired, as was that of CD4+ T cells. In conclusion, γδ T-cell expansion may act as a compensatory mechanism to combat viral infection, providing immune protection in immunocompromised individuals.

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Congenital epidermodysplasia verruciformis (CEV) is a Genodermatosis linked to different inheritance patterns and mutations of the EVER1/TMC6 and EVER2/TMC8 genes. There is an acquired form (AEV) associated with immunodeficiency states, including human immunodeficiency virus (HIV) infection; however, the literature about AEV is limited and imprecise, so a systematic review was performed. A search of the main databases from 1975 to 2021 identified 126 studies, of which 80 met the inclusion criteria. The diagnosis of AEV is complex due to atypical manifestations and locations, it requires a mean follow-up of 7 years, and the lesions do not change with ART therapy, CD4 count, or viral load. Histopathological findings are variable depending on the location of the lesions. HPV 5 remains the serotype most frequently associated with AEV and CEV, although HPV 20 is more frequent than HPV 8 in AEV. Most treatments have low efficacy, the most described are glycolic acid 15%, 5-fluorouracil 5%, imiquimod 5%, and topical retinoids all of them in monotherapy or combined with cryotherapy. Other alternatives include topical cidofovir and systemic retinoids with variable results. The oncologic prognosis is still inconclusive; however, the development of squamous cell carcinoma and melanoma are frankly lower concerning CEV. This review opens new opportunities for future research. Additionally, we provide clear and useful key points for the practice of dermatologists and all professionals treating HIV patients around the world.

Epidermodysplasia verruciformis (EV) is a rare genetic skin disorder that is characterized by the development of papillomavirus-induced skin lesions that can progress to squamous cell carcinoma (SCC). Certain high-risk, cutaneous β-genus human papillomaviruses (β-HPVs), in particular HPV5 and HPV8, are associated with inducing EV in individuals who have a homozygous mutation in one of three genes tied to this disease: EVER1, EVER2, or CIB1. EVER1 and EVER2 are also known as TMC6 and TMC8, respectively. Little is known about the biochemical activities of EVER gene products or their roles in facilitating EV in conjunction with β-HPV infection. To investigate the potential effect of EVER genes on papillomavirus infection, we pursued in vivo infection studies by infecting Ever2-null mice with mouse papillomavirus (MmuPV1). MmuPV1 shares characteristics with β-HPVs including similar genome organization, shared molecular activities of their early, E6 and E7, oncoproteins, the lack of a viral E5 gene, and the capacity to cause skin lesions that can progress to SCC. MmuPV1 infections were conducted both in the presence and absence of UVB irradiation, which is known to increase the risk of MmuPV1-induced pathogenesis. Infection with MmuPV1 induced skin lesions in both wild-type and Ever2-null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between Ever2-null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in Ever2-null mice compared with wild-type mice. These studies demonstrate that Ever2-null mice infected with MmuPV1 do not exhibit the same phenotype as human EV patients infected with β-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent β-genus human papillomavirus (β-HPV) skin infections, which can progress to skin cancer. To investigate how EVER2 confers protection from papillomaviruses, we infected the skin of homozygous Ever2-null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected Ever2-null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these Ever2-null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in Ever2-null mice, indicating that mouse EVER2 does not confer protection from papillomaviruses. These findings suggest that there are functional differences between MmuPV1 and β-HPVs and/or between mouse and human EVER2.

OBJECTIVE: The purpose of this focused review is to discuss unusual presentations of viral infections in the context of specific inborn errors of immunity. We will discuss hyper immunoglobulin E (IgE) syndromes, epidermodysplasia verruciformis, and X-linked agammaglobulinemia as examples of inborn errors of immunity associated with specific presentations of viral infection and disease.
RESULTS: Advances in both genetic and viral diagnostics have broadened our understanding of viral pathogenesis in the setting of immune dysfunction and the variable phenotype of inborn errors of immunity. Dedicator of cytokinesis 8 (DOCK8) deficiency is now recognized as an inborn error of immunity within the hyper IgE syndrome phenotype and is associated with unusually aggressive cutaneous disease caused by herpes simplex and other viruses. Studies of patients with epidermodysplasia verruciformis have proven that rarely detected human papillomavirus subtypes may cause malignancy in the absence of adequate host defenses. Finally, patients with X-linked agammaglobulinemia may remain at risk for severe and chronic viral infections, even as immune globulin supplementation reduces the risk of bacterial infection.
CONCLUSIONS: Susceptibility to viral infections in patients with inborn errors of immunity is conferred by specific, molecular defects. Recurrent, severe, or otherwise unusual presentations of viral disease should prompt investigation for an underlying genetic defect.

UNASSIGNED: Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis due to mutations in EVER1 and EVER2 genes. The genetic profile of Indian patients with EV has not been previously studied. This report describes the clinical presentation and molecular analysis of a family with EV. Using genomic DNA from two affected probands and healthy controls (two other siblings), conventional polymerase chain reaction (PCR) was conducted with novel primer sets designed to amplify the coding and splice-site regions in the genes EVER1 and EVER 2 . This revealed no amplification with a primer set for exons 16 to 18 in the EVER1 gene of both the probands. Subsequently, long-range PCR spanning the length of exon 15-20 and next-generation sequencing demonstrated a homozygous deletion of 2078 bp in the EVER1 gene ( EVER1 :c.2072_2278del). Screening the family revealed the same homozygous deletion (similar to index cases) in two other affected siblings. The parents and two asymptomatic siblings were heterozygous carriers for the deletion while one healthy sibling was negative. These results were validated with Sanger sequencing. This deletion in exons 17 and 18 of the EVER1 gene results in a frameshift, followed by a premature termination resulting in a severe phenotype. The identification and validation of this large deletion was detected using stepwise amplicon-based target enrichment and long-range PCR, respectively. In this family, this simple strategy greatly enhanced genetic counseling as well as early genetic diagnosis and screening. However, functional assays and larger studies are required to characterize and validate the genetic diversity among Indians with EV.

Human papillomavirus type 8 (HPV8), a cutaneous genus beta HPV type, has co-carcinogenic potential at sun-exposed sites in patients suffering from the inherited skin disease epidermodysplasia verruciformis (EV). We had previously shown that Langerhans cells responsible for epithelial immunosurveillance were strongly reduced at infected sites and that the HPV8 E7 protein interferes with the CCAAT/enhancer-binding protein (C/EBP)β to suppress the Langerhans cell chemokine CCL20. At the same time, however, we observed that EV lesions are heavily infiltrated with inflammatory immune cells, which is similar to the situation in HPV8 E6 transgenic mice. To identify critical inflammatory factors, we used a broad multiplex approach and found that the monocyte attracting chemokine CCL2 was significantly and strongly induced by HPV8 E6 but not E7-expressing HaCaT cells, which were used as a model for UV-damaged skin keratinocytes. Conditioned media from HPV8 E6-expressing keratinocytes enhanced CCL2-receptor (CCR2)-dependent monocyte recruitment in vitro, and macrophages predominated in the stroma but were also detected in the epidermal compartment of EV lesions in vivo. CCL2 induction by HPV8 E6 was even stronger than stimulation with the proinflammatory cytokine TNF-α, and both HPV8 E6 and TNF-α resulted in substantial suppression of the transcription factor C/EBPα. Using RNAi-mediated knockdown and overexpression approaches, we demonstrated a mechanistic role of the recently identified C/EBPα/miR-203/p63 pathway for HPV8 E6-mediated CCL2 induction at protein and transcriptional levels. Epithelial co-expression of p63 and CCL2 was confirmed in HPV8 E6-expressing organotypic air-liquid interface cultures and in lesional EV epidermis in vivo. In summary, our data demonstrate that HPV8 oncoproteins actively deregulate epidermal immune homeostasis through modulation of C/EBP factor-dependent pathways. While HPV8 E7 suppresses immunosurveillance required for viral persistence, the present study provides evidence that E6 involves the stemness-promoting factor p63 to support an inflammatory microenvironment that may fuel carcinogenesis in EV lesions.

Most tumors are caused by inherited or acquired genetic changes. However, a subset of tumors is driven by viral infection including Kaposi sarcoma, nasopharyngeal carcinoma, and others. Human papillomavirus (HPV) is an especially common cause of epithelial cancers and hyperplasias. Epidermodysplasia verruciformis (EDV) is a rare type of HPV infection with characteristic histopathologic features and a unique spectrum of HPV subtypes. We report here a distinctive form of EDV-associated eccrine neoplasia. Seven tumors from two patients were analyzed and show highly uniform features including multiple clustered clinical lesions, multifocal epidermal origin, eccrine differentiation with close association with the acrosyringium, an anastomosing growth pattern, and a bland monotonous poroid-to-basaloid cytomorphology. Clinical follow-up for one patient has been benign to date. These tumors show strong similarity to two previously reported cases, suggesting that this type of EDV-associated eccrine neoplasia may represent a rare but reproducible form of skin adnexal tumor with distinctive clinicopathologic features.

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UNASSIGNED: Epidermodysplasia verruciformis is a rare autosomal recessive genodermatosis. Clinical manifestations might be helpful in the diagnosis of this disease. However, the final diagnosis is made after a genetic and histological study. Acquired epidermodysplasia verruciformis is a form of epidermodysplasia verruciformis described in patients with compromised cell-mediated immunity.
UNASSIGNED: A 42-year-old female with a history of a pain and itch on the soles and palms started a year ago. There were multiple flat papules on the dorsal hands, scarring alopecia, malar rash, oral ulcers, Raynaud phenomenon, and palpable purpura. A histological examination confirmed the diagnosis of epidermodysplasia verruciformis.
UNASSIGNED: Epidermodysplasia verruciformis is an uncommon disease that affects the immune system. The coexistence of systemic lupus erythematosus and epidermodysplasia verruciformis is rarely reported in the medical literature. This paper reports a rare case in which these two diseases have coexisted.
UNASSIGNED: This publication aims to document this rare case and highlight the ideal criteria in diagnosing and treating epidermodysplasia verruciformis.