RESUMEN
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 ß-genus human papillomaviruses (ß-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 ß-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 ß-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 ß-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent ß-genus human papillomavirus (ß-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 ß-HPVs and/or between mouse and human EVER2.
Asunto(s)
Epidermodisplasia Verruciforme , Ratones Noqueados , Infecciones por Papillomavirus , Animales , Ratones , Epidermodisplasia Verruciforme/virología , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Papillomaviridae/genética , Papillomaviridae/patogenicidad , Betapapillomavirus/genética , Betapapillomavirus/patogenicidad , Humanos , Susceptibilidad a Enfermedades , Femenino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genéticaRESUMEN
ABSTRACT: 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.
Asunto(s)
Epidermodisplasia Verruciforme , Proteínas de la Membrana , Linaje , Adulto , Humanos , Masculino , Análisis Mutacional de ADN , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Mutación del Sistema de Lectura , Predisposición Genética a la Enfermedad , Homocigoto , India , Proteínas de la Membrana/genética , Fenotipo , Eliminación de SecuenciaRESUMEN
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.
Asunto(s)
Epidermodisplasia Verruciforme , Infecciones por Papillomavirus , Sarcoma de Kaposi , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Neoplasias Cutáneas/complicaciones , Papillomaviridae/genéticaRESUMEN
CONTEXT.: There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. OBJECTIVES.: To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and ß human papillomavirus (α-HPV and ß-HPV) genotypes, and describe relevant underlying genetic mutations. DESIGN.: Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. RESULTS.: Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and ß-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. CONCLUSIONS.: We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and ß-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.
Asunto(s)
Alphapapillomavirus , Coinfección , Epidermodisplasia Verruciforme , Genotipo , Mutación , Infecciones por Papillomavirus , Humanos , Femenino , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/virología , Epidermodisplasia Verruciforme/patología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/patología , Estudios Retrospectivos , Alphapapillomavirus/genética , Adulto , Coinfección/virología , Coinfección/genética , Coinfección/patología , Neoplasias de la Vulva/virología , Neoplasias de la Vulva/genética , Neoplasias de la Vulva/patología , Persona de Mediana Edad , Betapapillomavirus/genética , Vulva/patología , Vulva/virología , Lesiones Intraepiteliales Escamosas/virología , Lesiones Intraepiteliales Escamosas/patología , Lesiones Intraepiteliales Escamosas/genética , Virus del Papiloma HumanoAsunto(s)
Enfermedad de Bowen , Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Fotoquimioterapia , Neoplasias Cutáneas , Humanos , Ácido Aminolevulínico/uso terapéutico , Epidermodisplasia Verruciforme/tratamiento farmacológico , Epidermodisplasia Verruciforme/complicaciones , Epidermodisplasia Verruciforme/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia.
Asunto(s)
Epidermodisplasia Verruciforme , Enfermedades de Inmunodeficiencia Primaria , Enfermedades de la Piel , Masculino , Humanos , Adolescente , Epidermodisplasia Verruciforme/diagnóstico , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Papillomaviridae , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Proteínas Serina-Treonina Quinasas , Péptidos y Proteínas de Señalización IntracelularRESUMEN
BACKGROUND: Epidermodysplasia verruciformis (EDV) is a rare cutaneous manifestation of human papilloma virus infection, which has a potential for malignant transformation. The characteristic histologic features of EDV may not always be present and may often be overlooked. The use of a panel of novel biomarkers may aid in differentiating EDV from their clinical and pathologic mimics. MATERIAL AND METHODS: We reviewed 20 cases histologically diagnosed as EDV from 2013 to 2022. Sections were reviewed for histopathologic features, and immunohistochemistry for p16 and Ki67 was performed. RESULTS: There were 20 cases, ranging in age from 6 to 52 years with a male predominance. Four patients were immunosuppressed, and 4 patients had a positive family history. The most common presentation was hypopigmented papules and macules. In all the cases, epidermal keratinocytes showed dysmaturation, enlargement, and a blue-gray cytoplasm. These changes were very focal and superficial in 15 cases (75%). Associated malignancies included carcinoma in situ (1), trichilemmoma (2), and trichilemmal carcinoma (1). The trichilemmal tumors were seen in 2 siblings. p16 was expressed in the parabasal and basal layers in 7 of 17 cases (41%), in keratinocytes with and without inclusions. Ki67 was increased and localized to suprabasal and parabasal keratinocytes in 15 of 17 cases (88%). CONCLUSION: Although striking and characteristic, the keratinocyte changes are often focal and superficial, requiring multiple step-sections. Association of EDV with familial trichilemmal neoplasms is a novel finding requiring further genetic testing. In cases of clinically suspected EDV with negative histopathologic findings, p16 and Ki67 seem useful as adjunct biomarkers and could serve as cost-effective alternatives to genotyping.
Asunto(s)
Epidermodisplasia Verruciforme , Neoplasias Cutáneas , Humanos , Masculino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Epidermodisplasia Verruciforme/patología , Antígeno Ki-67 , Neoplasias Cutáneas/patología , Queratinocitos/patología , Transformación Celular NeoplásicaAsunto(s)
Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Epidermodisplasia Verruciforme/diagnóstico , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Proteínas de la Membrana/genética , Mutación , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaAsunto(s)
Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Neoplasias Cutáneas , Humanos , Epidermodisplasia Verruciforme/diagnóstico , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Mutación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas de la Membrana/genéticaRESUMEN
HPVs are DNA viruses include approximately 450 types that are classified into 5 genera (α-, ß-, γ-, µ-, and ν-HPV). The γ- and ß-HPVs are present in low copy numbers in healthy individuals; however, in patients with an inborn error of immunity, certain species of ß-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either typical or atypical. Manifestations of typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to ß-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, to RNA extracted from normal-appearing skin and wart samples of patients with typical EV to explore the viral and human genetic determinants. In 26 patients, 9 distinct biallelic mutations were detected in TMC6, TMC8, and CIB1, 7 of which are previously unreported to our knowledge. Additionally, 20 different HPV species, including 3 α-HPVs, 16 ß-HPVs, and 1 γ-HPV, were detected, 8 of which are reported here for the first time to our knowledge in patients with EV (ß-HPV-37, -47, -80, -151, and -159; α-HPV-2 and -57; and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.
Asunto(s)
Epidermodisplasia Verruciforme , Infecciones por Papillomavirus , Humanos , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Infecciones por Papillomavirus/genética , Transcriptoma , Viroma , Proteínas de la Membrana/genéticaRESUMEN
Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes individuals to persistent infection with ß-human papillomavirus (HPV) genotypes. The term EDV acanthoma may be applied to lesions with incidental findings of EDV-defining histopathological features without clinical signs of EDV. We report a case of HPV-14- and -21-positive EDV acanthoma arising in association with condyloma in a female patient with a history of low-grade squamous intraepithelial lesion of the cervix positive for high-risk HPV (non-16/18), chronic kidney disease, and systemic lupus erythematosus. The patient had no family or personal history of EDV, but the patient was on immunosuppressive therapy with mycophenolate mofetil and prednisone. A biopsy specimen from one of the perianal lesions revealed histopathologic changes consistent with EDV in the setting of condyloma. Molecular testing showed HPV-14 and -21, which supported the coexistence of condyloma with EDV acanthoma.
Asunto(s)
Acantoma , Condiloma Acuminado , Epidermodisplasia Verruciforme , Infecciones por Papillomavirus , Neoplasias Cutáneas , Humanos , Femenino , Acantoma/complicaciones , Virus del Papiloma Humano , Epidermodisplasia Verruciforme/complicaciones , Epidermodisplasia Verruciforme/patología , Infecciones por Papillomavirus/patología , Condiloma Acuminado/complicaciones , Papillomaviridae , Neoplasias Cutáneas/complicacionesAsunto(s)
Epidermodisplasia Verruciforme , Proteínas de la Membrana , Neoplasias Cutáneas , Humanos , Codón sin Sentido , Epidermodisplasia Verruciforme/complicaciones , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas de la Membrana/genéticaRESUMEN
Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human beta papillomaviruses and a high rate of progression to squamous cell carcinoma on sun-exposed skin. The majority of EV cases are caused by homozygous mutation in TMC8. The peripheral blood mononuclear cells from a patient carrying homozygous mutation of the TMC8 gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. The homozygous mutation in TMC8 will cause the abnormal splicing variant, which is known to associated with EV. The established human induced pluripotent cell line will enable proper in vitro disease modelling of EV.
Asunto(s)
Epidermodisplasia Verruciforme , Células Madre Pluripotentes Inducidas , Humanos , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Células Madre Pluripotentes Inducidas/patología , Leucocitos Mononucleares/patología , Homocigoto , Mutación/genética , Proteínas de la Membrana/genéticaRESUMEN
ABSTRACT: Human papilloma virus (HPV) is the causative agent for a variety of cutaneous lesions including verruca vulgaris (VV) and epidermodysplasia verruciformis (EDV). There are more than 200 known genotypes of HPV, and specific HPV types are associated with different clinical manifestations and malignant potentials. Herein, we describe a case of a 43-year-old immunocompetent woman who presented with morphologically distinct lesions that were most consistent with EDV on clinical examination. However, further histopathological and viral analysis confirmed the lesions as HPV-57-positive VV. The risk of malignant transformation, and therefore treatment and surveillance, is dramatically different in VV versus EDV. Therefore, this case highlights the importance of a proper histopathological diagnosis with HPV viral testing when clinical presentations may vary or mimic other diseases.
Asunto(s)
Alphapapillomavirus , Epidermodisplasia Verruciforme , Infecciones por Papillomavirus , Verrugas , Adulto , Alphapapillomavirus/genética , ADN Viral , Epidermodisplasia Verruciforme/patología , Femenino , Humanos , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/patologíaRESUMEN
Acquired epidermodysplasia verruciformis is a rare disease. It can develop in immunocompromised patients due to infection with human papillomaviruses. Because such patients are at high risk of developing cutaneous squamous cell carcinoma, timely diagnosis and regular monitoring of the patient is essential. Here we present the case of a 46-year-old male patient with acquired epidermodysplasia verruciformis occurring 5 years after a kidney transplantation. A skin biopsy detected human papillomavirus genotype 20 with low oncogenic potential. Accordingly, a follow-up interval of 1 year was determined. He was instructed to follow strict photoprotection and to visit earlier if atypical lesions appeared. Overall, our case emphasizes the consideration of possible squamous cell carcinoma in such patients and the importance of appropriate preventive measures.
Asunto(s)
Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Trasplante de Riñón , Neoplasias Cutáneas , Epidermodisplasia Verruciforme/etiología , Epidermodisplasia Verruciforme/patología , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Papillomaviridae/genética , Neoplasias Cutáneas/etiologíaRESUMEN
Epidermodysplasia verruciformis (EV) is a rare cutaneous pre-cancerous condition characterized by presence of flat, scaly macules, verruca-like papillomatous papules, seborrheic keratosis-like lesions, and pink-red pityriasis versicolor-like macules. The disease is caused by abnormal susceptibility to certain specific beta-HPV subtypes, most commonly 5 and 8. Classic EV is genetically determined, but in immunocompromised individuals, an acquired form can occur. Only 48 cases of acquired EV (AEV) in people living with HIV have been described. We describe a case of AEV in a 36-year-old HIV-positive man with an history of stable optimal CD4 cell count and undetectable HIV viral load. The AEV significantly deteriorated after the administration of the second dose of the quadrivalent anti-HPV vaccine and did not improve despite local treatment, anti-HPV vaccination completion, and persistently optimal combined antiretroviral treatment adherence. To the best of our knowledge, this is the first report of an AEV deterioration with a clinical and temporal pattern mimicking an immune reconstitution inflammatory syndrome (IRIS) following anti-HPV vaccination, instead of low CD4 count restoration. After reviewing the current literature, we have hypothesized a vaccine-mediated IRIS-like phenomenon in the pathogenesis of the disease.
Asunto(s)
Epidermodisplasia Verruciforme , Infecciones por VIH , Síndrome Inflamatorio de Reconstitución Inmune , Adulto , Epidermodisplasia Verruciforme/patología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/complicaciones , Masculino , Papillomaviridae , Vacunación/efectos adversosRESUMEN
The vast majority of primary immunodeficiencies (PIDs) occur due to the defects in cells originating from hematopoietic stem cells, while in some PIDs, there are defects in various genes responsible for non-leucocyte immune response such as seen in epidermodysplasia verruciformis (EV). EV caused by the mutations in TMC6, TMC8, and CIB1 genes is called "typical." "Atypical" EV may develop in patients with primary immunodeficiencies originating from hematopoietic stem cells, which include severe T-cell failure, caused by inactivating biallelic mutations of STK4, RHOH, CORO1A, ITK, TPP2, DCLRE1C, LCK, RASGRP1, or DOCK8 genes. Here, we present a family with TMC8 gene mutation leading to disseminated epidermodysplasia verruciformis including laryngeal papilloma and recurrent cutaneous squamous cell carcinomas. Typical EV with impaired local, keratinocyte-intrinsic immune response should be considered when routine immunological examinations are normal in patients presenting with clinical signs of EV. Although it is not possible to prevent EV lesions, early and appropriate surveillance for malignancy is mandatory.
Asunto(s)
Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Papiloma , Neoplasias Cutáneas , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patología , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Laríngeas , Proteínas de la Membrana/genética , Mutación , Recurrencia Local de Neoplasia , Proteínas Serina-Treonina Quinasas , Neoplasias Cutáneas/genéticaRESUMEN
A transgender female in her 40s with history of HIV and testicular cancer status post-genital X-irradiation presented with a perianal mass and pruritic rash across her chest. Physical examination revealed a bulky, verrucous tumor protruding outward from the anus involving the medial buttocks. Examination of the chest and arms showed numerous guttate, pink, flat-topped papules coalescing into plaques. Clinically and histologically the lesions were consistent with Buschke-Löwenstein condyloma (BLC) and acquired epidermodysplasia verruciformis (AEDV). Buschke-Löwenstein condyloma incisional biopsy tested negative for common low- and high-risk human papillomavirus (HPV) subtypes, including 6, 11, 16, and 18, possibly implicating beta HPV subtype or a less common pathogenic subtype. The patient underwent abdominoperineal resection of the BLC, which tested positive for low-risk HPV subtypes, suggesting the possibility of multiple implicated HPV subtypes in the same tumor. This case demonstrates a possible role of beta HPV or rarer HPV subtypes in the pathogenesis of verrucous carcinoma, particularly in the setting of immunosuppression.