Epidermodysplasia verruciformis-associated eccrine neoplasm: a rare entity with distinctive clinical and histopathologic features.

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.

STK4 deficiency and epidermodysplasia verruciformis-like lesions: A case report.

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.

Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review.

PURPOSE: Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI. METHODS: We conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI. RESULTS: The inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive inheritance predominated (69%). PHPVI onset age was 10.8 ± 8.6 years, with an interquartile range of 5 to 14 years. GATA2,IL2RG,DOCK8, CXCR4, TMC6, TMC8, and CIB1 are the most frequently reported PHPVI-associated genes with strong causality. Most genes (74 out of 83) belong to a catalog of 485 inborn errors of immunity-related genes, and 40 genes (54%) are represented in the nonsyndromic and syndromic combined immunodeficiency categories. CONCLUSION: PHPVI has at least 83 monogenic etiologies and a genetic diagnosis is essential for effective management.

Recent advances in cutaneous HPV infection.

More than 200 types of human papillomavirus (HPV) have been reported to date and have been associated with various dermatological diseases. Among dermatological diseases, viral verrucae are the most commonly reported to be associated with HPV. Epidermodysplasia verruciformis (EV) consists of three types: typical EV is an autosomal recessive genetic disorder with TMC6/TMC8 gene mutations, atypical EV develops due to various gene mutations that cause immunodeficiency, and acquired EV develops due to acquired immunodeficiency. Generalized verrucosis differs from EV in that it involves numerous verrucous nodules (mainly on the limbs), histopathologically no blue cells as seen in EV, and infection with cutaneous α-HPVs as well as ß-HPVs. HPV-induced skin malignancies include squamous cell carcinoma (SCC) caused by ß-HPV (especially HPV types 5 and 8) in EV patients, organ transplant recipients, and healthy individuals, and SCC of the vulva and nail unit caused by mucosal high-risk HPV infection. Carcinogenesis of ß-HPV is associated with sunlight. Mucosal high-risk HPV-associated carcinomas may also be sexually transmitted. We focused on Bowen's disease of the nail, which has been the subject of our research for a long time and has recently come to the fore in the field of dermatology.

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, ß-, and γ-HPV infections.

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.

Establishment of a human induced pluripotent stem cell line, KMUGMCi005-A, from a patient with Epidermodysplasia verruciformis (EV) bearing homozygous splicing donor site mutation in the TMC8 gene.

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.

TMC8 mutation in a Turkish family with epidermodysplasia verruciformis including laryngeal papilloma and recurrent skin carcinoma.

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.

Recalcitrant Warts, Epidermodysplasia Verruciformis, and the Tree-Man Syndrome: Phenotypic Spectrum of Cutaneous Human Papillomavirus Infections at the Intersection of Genetic Variability of Viral and Human Genomes.

Human papillomavirus (HPV) infections can cause common warts, which usually resolve spontaneously or become recalcitrant, resistant to multiple treatments. In rare cases, they transform into cutaneous giant horns resulting in the tree-man syndrome (TMS). Defective ß-HPVs can cause flat warts in epidermodysplasia verruciformis (EV), a genetic disorder. In typical EV, limited to the skin, the mutated genes are critical for keratinocyte-intrinsic immunity, whereas atypical, syndromic EV involves genes controlling T cells. Inborn errors of immunity due to mutations in distinct genes underlying recalcitrant warts and the α-HPV2‒driven TMS have been identified, all disrupting T-cell immunity. Collectively, these observations attest to the wide phenotypic spectrum of cutaneous infections caused by different HPV types at the intersection of the genetic diversity of the viral and human genomes.

Epidermodysplasia verruciformis: report of two patients with autosomal dominant inheritance.

Epidermodysplasia verruciformis is a rare genodermatosis associated with mutations in the EVER1/TMC6 and EVER2/TMC8 genes. The inheritance is considered to be autosomal recessive, but reports suggesting an autosomal dominant inheritance indicate disease genetic heterogeneity. Its onset occurs in early childhood and presents as a combination of pityriasis versicolor-like, flat wart-like and seborrheic keratosis-like lesions, with a potential for malignant transformation, mainly squamous cell carcinoma.

Gene expression is stable in a complete CIB1 knockout keratinocyte model.

Epidermodysplasia verruciformis (EV) is a genodermatosis characterized by the inability of keratinocytes to control cutaneous ß-HPV infection and a high risk for non-melanoma skin cancer (NMSC). Bi-allelic loss of function variants in TMC6, TMC8, and CIB1 predispose to EV. The correlation between these proteins and ß-HPV infection is unclear. Its elucidation will advance the understanding of HPV control in human keratinocytes and development of NMSC. We generated a cell culture model by CRISPR/Cas9-mediated deletion of CIB1 to study the function of CIB1 in keratinocytes. Nine CIB1 knockout and nine mock control clones were generated originating from a human keratinocyte line. We observed small changes in gene expression as a result of CIB1 knockout, which is consistent with the clearly defined phenotype of EV patients. This suggests that the function of human CIB1 in keratinocytes is limited and involves the restriction of ß-HPV. The presented model is useful to investigate CIB1 interaction with ß-HPV in future studies.

Multiple flat-topped scaly violaceous papules.

Epidermodysplasia verruciformis (EV) is an autosomal recessive genodermatosis characterized by susceptibility to beta-genus human papillomavirus (HPV) infection. Owing to TMC6/EVER1 and TMC8/EVER2 mutations that lead to abnormal transmembrane channels in the endoplasmic reticulum involved in immunological pathways, keratinocytes cannot combat infection from non-pathogenic HPV strains. Mutations involving RHOH, MST-1, CORO1A, and IL-7 have also been associated with EV in patients without TMC6 or TMC8 mutations. We highlight a 27-year-old man with multiple violaceous flat-topped papules with scale and irregular borders distributed on his chest, extremities, abdomen, and back. The striking physical examination and the subsequent biopsy findings of enlarged nests of cells in the granular and spinous layers with blue-gray cytoplasm and keratohyaline granules confirmed the diagnosis. We conclude with a brief discussion on the differential diagnosis, which includes confluent and reticulated papillomatosis, Darier disease, and disseminated superficial actinic porokeratosis.

Inherited Interleukin 2-Inducible T-Cell (ITK) Kinase Deficiency in Siblings With Epidermodysplasia Verruciformis and Hodgkin Lymphoma.

Biallelic mutations in the ITK gene cause a T-cell primary immunodeficiency with Epstein-Barr virus (EBV)-lymphoproliferative disorders. We describe a novel association of a homozygous ITK mutation with ß-human papillomavirus (HPV)-positive epidermodysplasia verruciformis. Thus, loss of function in ITK can result in broad dysregulation of T-cell responses to oncogenic viruses, including ß-HPV and EBV.

Diagnosis of epidermodysplasia verruciformis: Two cases highlighting the role of direct HPV L1 gene sequencing.

Epidermodysplasia verruciformis (EV) is a rare skin disease characterized by the development of multiple flat warts with the potential for malignant transformation. Patients are susceptible to human papillomavirus (HPV) infection that develops in a background of either a genetic or acquired immunodeficiency predisposing patients to infection with specific HPV types that are ubiquitous but generally non-pathogenic in healthy individuals. There is no standard clinical methodology for determining the causative HPV from patients with suspected EV. Here, we report the diagnostic workup of two EV cases and describe the use of L1 gene Sanger sequencing as a specific method to accurately identify the causative HPV genotype and confirm the diagnosis of EV.