Idiopathic Granulomatous Vulvitis: A Case Report on a Rare Disease.

Idiopathic granulomatous vulvitis is an uncommon anogenital area disease described in the last few decades. It causes an inflammatory reaction that culminates in swelling and possibly distortion of the female anogenital area. Many reported cases consider this non-infectious entity the genital counterpart to granulomatous cheilitis. We here present a 64 years old female patient with idiopathic granulomatous vulvitis co-existing with lipodermatosclerosis, with the excellent response of the former condition to hydroxychloroquine and potent topical steroids.

Skin Manifestations Among Patients Admitted with COVID-19: A Cross-Sectional Study at a University-Based Tertiary Hospital in Jordan.

Background: COVID-19 pandemic hit the entire world with severe health and economic consequences. Although the infection primarily affected the respiratory system, it was soon recognized that COVID-19 has a multi-systemic component with various manifestations including cutaneous involvement. Objective: The main objective of this study is to assess the incidence and patterns of cutaneous manifestations among moderate-to-severe COVID-19 patients who required hospitalization and whether there was a prognostic indication for cutaneous involvement and the outcome in terms of recovery or death. Methods: This is a cross-sectional observational study that included inpatients who were diagnosed with a moderate or severe COVID-19 infection. The demographic and clinical data of patients were assessed including age, sex, smoking, and comorbidities. All patients were examined clinically for the presence of skin manifestations. Patients were followed for the outcome of COVID-19 infection. Results: A total of 821 patients (356 females and 465 males) aged 4-95 years were included. More than half of patients (54.6%) aged >60 years. A total of 678 patients (82.6%) had at least one comorbid condition, mostly hypertension and diabetes mellitus. Sixty-two patients (7.55%) developed rashes; 5.24% cutaneous and 2.31% oral. The rashes were then grouped into five major types: group A, Exanthema: morbilliform, papulovesicular, varicella-like. Group B, Vascular: Chilblain-like lesions, purpuric/petechial, livedoid lesions. Group C, Reactive erythemas: Urticaria, Erythema multiforme. Group D, other skin rashes including flare-up of pre-existing disease, and O for oral involvement. Most patients (70%) developed rash after admission. The most frequent skin rashes were reactive erythema (23.3%), followed by vascular (20.9%), exanthema (16.3%), and other rashes with flare-ups of pre-existing diseases (39.5%). Smoking and loss of taste were associated with the appearance of various skin rashes. However, no prognostic implications were found between cutaneous manifestations and outcome. Conclusion: COVID-19 infection may present with various skin manifestations including worsening of pre-existing skin diseases.

Comparison of the efficacy of Tacrolimus 0.1% ointment and Tacrolimus 0.1% plus topical pseudocatalase/superoxide dismutase gel in children with limited vitiligo: a randomized controlled trial.

BACKGROUND: The pathogenesis of vitiligo is complex and multifactorial, accumulating evidence of increased oxidative stress and reduction in catalase levels in vitiligo patients has been shown, hence, pseudocatalase/superoxide dismutase (PSD) gel has been used as treatment option for vitiligo. AIM: To assesses the synergic effect of PSD when combines with Tacrolimus 0.1% ointment versus Tacrolimus 0.1% alone. METHOD: A randomized controlled trial that included 49 children with vitiligo with limited area (10% or less). Patients were randomized into two groups: Group 1 (24 patients) were treated only with Tacrolimus 0.1% ointment whereas Group 2 (25 patients) were treated with Tacrolimus 0.1% ointment plus PSD. Degree of repigmentation compared to baseline was assessed at 3, 6, and 9 months. RESULTS: The median age was 10.05 years (range 2-18). The percentages of pigmentation on 3, 6, and 9 months for Group 1 were 23.9%, 40.4%, and 60%, respectively and for Group 2 were 23.2%, 40.7%, and 62.4%, respectively. There was no significant difference according to repigmentation percentages between the two groups (p > .86, p > .97, and p > .78, respectively). CONCLUSIONS: The results showed that the addition of PSD to Tacrolimus ointment in children with limited vitiligo was not associated with any therapeutic benefit.

Global gene methylation profiling of common warts caused by human papillomaviruses infection.

Infection with the human papillomaviruses (HPV) often involves the epigenetic modification of the host genome. Despite its prevalence among the population, host genome methylation in HPV-induced warts is not clearly understood. In this study, genome-wide methylation profiling was carried out on paired healthy skin and wart samples in order to investigate the effects that benign HPV infection has on gene methylation status. To overcome this gap in knowledge, paired wart (n = 12) and normal skin (n = 12) samples were obtained from Arab males in order to perform DNA extraction and subsequent genome-wide methylation profiling on the Infinium Methylation EPIC Bead Chip microarray. Analysis of differential methylation revealed a clear pattern of discrimination between the wart and normal skin samples. In warts, the most differentially methylated (DM) genes included long non-coding RNAs (AC005884, AL049646.2, AC126121.2, AP001790.1, and AC107959.3), microRNAs (MIR374B, MIR596, MIR1255B1, MIR26B, and MIR196A2),snoRNAs (SNORD114-22, SNORD70, and SNORD114-31), pseudogenes (AC069366.1, RNU4ATAC11P, AC120057.1, NANOGP3, AC106038.2, TPT1P2, SDC4P, PKMP3, and VN2R3P), and protein-coding genes (AREG, GJB2, C12orf71, AC020909.2, S100A8, ZBED2, FABP7, and CYSLTR1). In addition, pathway analysis revealed that, among the most differentially methylated genes, STAT5A, RARA, MEF2D, MAP3K8, and THRA were the common regulators. It can be observed that HPV-induced warts involve a clear and unique epigenetic alteration to the host genome.

Impact of COVID-19 pandemic on the continuity of care for dermatologic patients on systemic therapy during the period of strict lockdown.

BACKGROUND: The world has changed dramatically since the COVID-19 pandemic began. Jordan was among countries which enforced early lock-down for most non-vital services. Health care was mainly directed to cope with COVID-19 cases. The pandemic posed challenges for all patients, including dermatology patients especially those on systemic treatments. This resulted in interruption of medical care and exacerbation of pre-existing skin diseases for many patients. MATERIAL AND METHODS: A cross-sectional, questionnaire-based study of dermatology patients on systemic treatment prior to corona pandemic. After lockdown was lifted, patients taking systemic treatments were evaluated for continuity of care during lockdown period and how that affected their skin condition. Demographic data, details of skin condition, continuity of care and impact on skin condition data were collected and analyzed. RESULTS: 154 patients (120 males, 34 females) were included. The majority (around 80%) of patients were unable to attend to dermatology clinics or do the needed lab monitoring. Around one fifth of patients had drug interruption mostly due to no access to hospital pharmacy. Most patients were using oral isotretinoin for acne, others include methotrexate and other immune suppressive agents. Patients with acne and oral isotretinoin treatment were more likely to continue their treatment during lockdown period. Amongst those who stopped treatment, around 42% had flare up of their disease. CONCLUSION: COVID-19 pandemic had an important impact on various aspects of care for dermatology patients especially those on systemic therapy. This study demonstrated limited access to specialist care, inability to do lab tests and discontinuation of treatment during lockdown. Some patients (42%) had flare up of their skin condition as a result.

Comparison of the Efficacy and Safety of Two Cryotherapy Protocols in the Treatment of Common Viral Warts: A Prospective Observational Study.

BACKGROUND: Cryotherapy (freezing by liquid nitrogen) is an effective and widely used method for treatment of common warts. Patients often need multiple sessions at variable intervals. Protocols used by different dermatologists vary in terms of freezing time, the number of cycles, and the intervals between sessions. AIM: To compare the efficacy (cure rates) and safety (complications, early and late) of two cryotherapy treatment protocols for common viral warts. METHOD: A prospective observational study was conducted; it involved 80 patients with common warts on the hands and feet who were treated with cryotherapy done by two dermatologists who use different protocols; group 1 (45 patients) were treated by a single cycle of 10 seconds of freezing at 2 weekly intervals, and group 2 (35 patients) received a single cycle of 20 seconds of freezing at 4-weeks intervals. The two protocols were compared in terms of cure rate and complications 1-2 months after the final treatment. Recurrence rate and late complications were assessed at 9-12 months after the final treatment. RESULTS: Group 1 patients achieved higher cure rate than group 2, 77.8% and 54.3%, respectively (P=0.001). Early (blistering) and late complications (dyspigmentation and scarring) were comparable in both groups. Pain score associated with protocol 1 (5.2/10) was less than protocol 2 (6.4/10) (P=0.004). Recurrence rate (17%) was comparable in both groups. Association between cure rate and duration of warts (P=0.022) and also association between cure rate and the mean number of warts (P=0.001) were demonstrated. CONCLUSIONS: Cryotherapy is an effective and safe treatment for common viral warts of hands and feet. The impact of shorter intervals on cure rate was more significant than increasing freezing time with longer intervals between freezing sessions. The study was approved by the local IRB committee (285-2018).

Genome-wide identification of methylated CpG sites in nongenital cutaneous warts.

BACKGROUND: Low-risk HPV infection has not been the subject of epigenetic investigation. The present study was carried out in order to investigate the methylation status of CpG sites in non-genital cutaneous warts. METHODS: Genomic DNA was extracted from 24 paired epidermal samples of warts and normal skin. DNA samples were bisulfite converted and underwent genome-wide methylation profiling using the Infinium MethylationEPIC BeadChip Kit. RESULTS: From a total of 844,234 CpG sites, 56,960 and 43,040 CpG sites were found to be hypo- and hypermethylated, respectively, in non-genital cutaneous warts. The most differentially methylated CpG sites in warts were located within the C10orf26, FAM83H-AS1, ZNF644, LINC00702, GSAP, STAT5A, HDAC4, NCALD, and EXOC4 genes. CONCLUSION: Non-genital cutaneous warts exhibit a unique CpG methylation signature.

Transcriptome analysis of HPV-induced warts and healthy skin in humans.

BACKGROUND: The human papillomaviruses (HPV) are a group of viruses that, depending on the strain, can cause cancer or the formation of benign growths known as warts. Scarce information exists with regard to the genetic nature of non-genital cutaneous warts induced by the human papillomavirus (HPV). METHODS: The main purpose of this study is to investigate the differences between the gene expression profiles of common warts and healthy skin in HPV-positive individuals by RNA sequencing on the Illumina HiSeq 2500. After obtaining shave biopsies of common warts and healthy skin from twelve Arab males, we were able to analyze the transcriptomes of 24 paired cases and controls. RESULTS: Common warts were found to possess a highly significant and unique molecular signature. Many of the most up-regulated (KRT16, EPGN, and ABCG4) and down-regulated genes (C15orf59, CYB561A3, and FCGRT) in warts were the subject of little investigation in the published literature. Moreover, the top 500 differentially expressed genes were found to be associated with immune and autoimmune pathways, such as the neutrophil degranulation, toll-like receptor 7/8 (TLR 7/8) cascade, toll-like receptor 9 (TLR9) cascade, and toll-like receptor 10 (TLR10) pathways, among others. CONCLUSIONS: Our findings are particularly important because they serve as the most comprehensive to date with regard to the modulation of human skin gene expression by HPV infection.

Epigenome-wide analysis of common warts reveals aberrant promoter methylation.

Epigenetic alteration of host DNA is a common occurrence in both low- and high-risk human papillomavirus (HPV) infection. Although changes in promoter methylation have been widely studied in HPV-associated cancers, they have not been the subject of much investigation in HPV-induced warts, which are a temporary manifestation of HPV infection. The present study sought to examine the differences in promoter methylation between warts and normal skin. To achieve this, DNA was extracted from 24 paired wart and normal skin samples and inputted into the Infinium MethylationEPIC BeadChip microarray. Differential methylation analysis revealed a clear pattern of hyper- and hypomethylation in warts compared to normal skin, and the most differentially methylated promoters were found within the EIF3EP2, CYSLTR1, C10orf99, KRT6B, LAMA4, and H3F3B genes as well as the C9orf30 pseudogene. Moreover, pathway analysis showed that the H3F3A, CDKN1A, and MAPK13 genes were the most common regulators among the most differentially methylated promoters. Since the tissue samples were excised from active warts, however, this differential methylation could either be a cellular response to HPV infection or an HPV-driven process to establish the wart and/or promote disease progression. Conclusively, it is apparent that HPV infection alters the methylation status of certain genes to possibly initiate the formation of a wart and maintain its presence.

Candidate Gene Analysis Of Alopecia Areata In Jordanian Population Of Arab Descent: A Case-Control Study.

BACKGROUND: Alopecia areata (AA) is a non-cicatricial patchy hair loss on the scalp, face or other parts of the body. AA was found to be responsive to immunosuppressive therapies, a finding that supports an autoimmune basis for the disease. Several genetic studies have shown the significance of immunological factors as key genetic components in AA. OBJECTIVE: In this study, we aimed to investigate the genetic association of 7 single-nucleotide polymorphisms (SNPs) within five candidate genes including TAP1, CXCL1, CXCL2, HSPA1B, and TNFα with AA susceptibility in the Jordanian Arab population. METHODS: A case-control genetic association study conducted in 152 patients and 150 healthy individuals was performed using the sequenom MassARRAY system (iPLEX GOLD) to genotype the selected SNPs. RESULTS: rs1800629 SNP of the TNFα gene was significantly associated with AA in the heterozygous and rare homozygous genotypes (P=0.022 and P=0.0079, respectively) with no linkage of the TAP1, CXCL1, CXCL2 and HSPA1B variants. CONCLUSION: This is the first study of its kind among the Jordanian population providing evidence of genetic association of the TNFα with AA susceptibility. Further genetic studies on Arab descent including other variants are required to clarify and strengthen the association of these genes with susceptibility to develop AA.

Gene Expression Profiling of MicroRNAs in HPV-Induced Warts and Normal Skin.

: Infection with the human papillomavirus (HPV) is a common occurrence among the global population, with millions of new cases emerging on an annual basis. Dysregulated microRNA (miRNA) expression is increasingly being identified to play a role in a number of different diseases, especially in the context of high-risk HPV infection. The present study investigated the miRNA expression profiles of warts induced by low-risk HPV. In warts, miR-27b, miR-24-1, miR-3654, miR-647, and miR-1914 were downregulated while miR-612 was upregulated compared to normal skin. Using miRTargetLink Human, experimentally supported evidence was obtained showing that miR-27b targeted the vascular endothelial growth factor C (VEGFC) and CAMP-responsive element binding protein 1 (CREB1) genes. The VEGFC and CREB1 genes have been reported to be involved in tumorigenesis and wart formation, respectively. Similarly, the oxidized low-density lipoprotein receptor 1 (OLR1) gene, which plays an important role in the humoral immunity of the skin, and the plexin D1 (PLXND1) gene, which is highly expressed in tumor vasculature, were both found to be common targets of miR-27b, miR-1914, and miR-612.

Assessment of Serum Vitamin D Levels in Patients with Vitiligo in Jordan: A Case-Control Study.

BACKGROUND: Low vitamin D serum levels have been associated with many autoimmune disorders and several other skin diseases. Vitiligo is an autoimmune disease characterized by destruction of melanocytes by immune mechanisms. Melanocytes express vitamin D receptors, and their function can be affected by vitamin D status. OBJECTIVES: The main objective of this study is to compare vitamin D levels in patients with vitiligo vs normal population and whether vitamin D deficiency is associated with vitiligo. METHODS: A case-control study was conducted. 100 vitiligo patients and 100 as controls were included in this study. Serum vitamin D level was measured for both vitiligo patients and controls, results were compared, and statistical analysis was done to compare the results. RESULTS: The median age of vitiligo cases was 23 years (ranges, 2-80). 58% of vitiligo patients were females. The median vitamin D level was not significantly different between the two groups (vitiligo = 14.1 (IQR 9.9-20.4) vs control = 16.5 (IQR 10.3-25.3) (P=0.28)). Most vitiligo cases and controls were found to have low levels of vitamin D (either insufficient 20-30 ng/mL or low <20 ng/mL). CONCLUSIONS: There was no significant difference in vitamin D levels in vitiligo patients compared to controls. However, vitamin D levels were generally low in both groups.

Genome-Wide CpG Island Methylation Profiles of Cutaneous Skin with and without HPV Infection.

HPV infection is one of the most commonly transmitted diseases among the global population. While it can be asymptomatic, non-genital HPV infection often gives rise to cutaneous warts, which are benign growths arising from the epidermal layer of the skin. This study aimed to produce a global analysis of the ways in which cutaneous wart formation affected the CpG island methylome. The Infinium MethylationEPIC BeadChip microarray was utilized in order to quantitatively interrogate CpG island methylation in genomic DNA extracted from 24 paired wart and normal skin samples. Differential methylation analysis was carried out by means of assigning a combined rank score using RnBeads. The 1000 top-ranking CpG islands were then subject to Locus Overlap Analysis (LOLA) for enrichment of genomic ranges, while signaling pathway analysis was carried out on the top 100 differentially methylated CpG islands. Differential methylation analysis illustrated that the most differentially methylated CpG islands in warts lay within the ITGB5, DTNB, RBFOX3, SLC6A9, and C2orf27A genes. In addition, the most enriched genomic region sets in warts were Sheffield's tissue-clustered DNase hypersensitive sites, ENCODE's segmentation and transcription factor binding sites, codex sites, and the epigenome sites from cistrome. Lastly, signaling pathway analysis showed that the GRB2, GNB1, NTRK1, AXIN1, and SKI genes were the most common regulators of the genes associated with the top 100 most differentially methylated CpG islands in warts. Our study shows that HPV-induced cutaneous warts have a clear CpG island methylation profile that sets them apart from normal skin. Such a finding could account for the temporary nature of warts and the capacity for individuals to undergo clinical remission.

Genome-Wide Tiling Array Analysis of HPV-Induced Warts Reveals Aberrant Methylation of Protein-Coding and Non-Coding Regions.

The human papillomaviruses (HPV) are a group of double-stranded DNA viruses that exhibit an exclusive tropism for squamous epithelia. HPV can either be low- or high-risk depending on its ability to cause benign lesions or cancer, respectively. Unsurprisingly, the majority of epigenetic research has focused on the high-risk HPV types, neglecting the low-risk types in the process. Therefore, the main objective of this study is to better understand the epigenetics of wart formation by investigating the differences in methylation between HPV-induced cutaneous warts and normal skin. A number of clear and very significant differences in methylation patterns were found between cutaneous warts and normal skin. Around 55% of the top-ranking 100 differentially methylated genes in warts were protein coding, including the EXOC4, KCNU, RTN1, LGI1, IRF2, and NRG1 genes. Additionally, non-coding RNA genes, such as the AZIN1-AS1, LINC02008, and MGC27382 genes, constituted 11% of the top-ranking 100 differentially methylated genes. Warts exhibited a unique pattern of methylation that is a possible explanation for their transient nature. Since the genetics of cutaneous wart formation are not completely known, the findings of the present study could contribute to a better understanding of how HPV infection modulates host methylation to give rise to warts in the skin.