Functional Genotype-Phenotype Associations in Recessive Dystrophic Epidermolysis Bullosa.

BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen (C7) function per updated literature, and subsequently categorized by degree of impact on C7 function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: 83 participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs. 72.7% medium-impact vs. 90.4% high-impact variants, p=0.002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (p=0.02), and 5.7-fold greater odds of death compared to medium-impact variants (p=0.05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Incidence of Nonkeratinocyte Skin Cancer After Breast Cancer Radiation Therapy.

Importance: Previous studies have suggested that radiation therapy may contribute to an increased risk of subsequent nonkeratinocyte (ie, not squamous and basal cell) skin cancers. Objective: To test the hypothesis that radiation therapy for breast cancer increases the risk of subsequent nonkeratinocyte skin cancers, particularly when these cancers are localized to the skin of the breast or trunk. Design, Setting, and Participants: This population-based cohort study used longitudinal data from the Surveillance, Epidemiology, and End Results (SEER) Program for January 1, 2000, to December 31, 2019. The SEER database includes population-based cohort data from 17 registries. Patients with newly diagnosed breast cancer were identified and were evaluated for subsequent nonkeratinocyte skin cancer development. Data analysis was performed from January to August 2023. Exposures: Radiation therapy, chemotherapy, or surgery for breast cancer. Main Outcomes and Measures: The primary outcomes were standardized incidence ratios (SIRs) for subsequent nonkeratinocyte skin cancer development from 2000 to 2019 based on treatment type (radiation therapy, chemotherapy, or surgery), skin cancer site on the body, and skin cancer subtype. Results: Among the 875 880 patients with newly diagnosed breast cancer included in this study, 99.3% were women, 51.6% were aged older than 60 years, and 50.3% received radiation therapy. A total of 11.2% patients identified as Hispanic, 10.1% identified as non-Hispanic Black, and 69.5% identified as non-Hispanic White. From 2000 to 2019, there were 3839 patients with nonkeratinocyte skin cancer, including melanoma (3419 [89.1%]), Merkel cell carcinoma (121 [3.2%]), hemangiosarcoma (104 [2.7%]), and 32 other nonkeratinocyte skin cancers (195 [5.1%]), documented to occur after breast cancer treatment. The risk of nonkeratinocyte skin cancer diagnosis after breast cancer treatment with radiation was 57% higher (SIR, 1.57 [95% CI, 1.45-1.7]) than that of the general population when considering the most relevant site: the skin of the breast or trunk. When risk at this site was stratified by skin cancer subtype, the SIRs for melanoma and hemangiosarcoma were both statistically significant at 1.37 (95% CI, 1.25-1.49) and 27.11 (95% CI, 21.6-33.61), respectively. Receipt of radiation therapy was associated with a greater risk of nonkeratinocyte skin cancer compared with chemotherapy and surgical interventions. Conclusions and Relevance: In this study of patients with breast cancer, an increased risk of melanoma and hemangiosarcoma after breast cancer treatment with radiation therapy was observed. Although occurrences of nonkeratinocyte skin cancers are rare, physicians should be aware of this elevated risk to help inform follow-up care.

Risk of Multiple Primary Cancers in Patients With Merkel Cell Carcinoma: A SEER-Based Analysis.

Importance: The risk of subsequent primary cancers after a diagnosis of cutaneous Merkel cell carcinoma (MCC) is not well established. Objective: To evaluate the risk of subsequent primary cancers after the diagnosis of a first primary cutaneous MCC. Design, Setting, and Participants: This cohort study analyzed data from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program from January 1, 2000, to December 31, 2019. In all, 6146 patients diagnosed with a first primary cutaneous MCC were identified. Main Outcomes and Measures: The primary outcome was the relative and absolute risks of subsequent primary cancers after the diagnosis of a first primary MCC, which were calculated using the standardized incidence ratio (SIR; ratio of observed to expected cases of subsequent cancer) and the excess risk (difference between observed and expected cases of subsequent cancer divided by the person-years at risk), respectively. Data were analyzed between January 1, 2000, and December 31, 2019. Results: Of 6146 patients with a first primary MCC diagnosed at a median (IQR) age of 76 (66-83) years, 3713 (60.4%) were men, and the predominant race and ethnicity was non-Hispanic White (5491 individuals [89.3%]). Of these patients, 725 (11.8%) developed subsequent primary cancers, with an SIR of 1.28 (95% CI, 1.19-1.38) and excess risk of 57.25 per 10 000 person-years. For solid tumors after MCC, risk was elevated for cutaneous melanoma (SIR, 2.36 [95% CI, 1.85-2.97]; excess risk, 15.27 per 10 000 person-years) and papillary thyroid carcinoma (SIR, 5.26 [95% CI, 3.25-8.04]; excess risk, 6.16 per 10 000 person-years). For hematologic cancers after MCC, risk was increased for non-Hodgkin lymphoma (SIR, 2.62 [95% CI, 2.04-3.32]; excess risk, 15.48 per 10 000 person-years). Conclusions and Relevance: This cohort study found that patients with MCC had an increased risk of subsequently developing solid and hematologic cancers. This increased risk may be associated with increased surveillance, treatment-related factors, or shared etiologies of the other cancers with MCC. Further studies exploring possible common etiological factors shared between MCC and other primary cancers are warranted.

Prevalence of Cosmetic Procedures among Lebanese Women.

Lebanese women have been portrayed as conceited and obsessed with physical appearance and its beautification through cosmetic procedures. Despite the pervasiveness of this notion, no formal studies have been conducted to assess the true prevalence of cosmetic procedures among Lebanese women. Additionally, no data exist to elucidate trends in popularity of cosmetic procedures over time. A cross-sectional study was conducted across Lebanese universities where surveys were distributed to women aged 18-31 years to estimate the prevalence of surgical, noninvasive, and dental cosmetic procedures in young Lebanese women. The collected survey data were analyzed using the Statistical Package for the Social Sciences (SPSS). In a sample of 877 women, 44% reported having undergone at least one cosmetic procedure in their lifetime. The most popular procedures performed were laser hair removal (32%), teeth whitening (14%), and rhinoplasty (9.3%). The obtained results revealed an increasing prevalence of cosmetic procedures, mirroring global trends. A variety of factors have contributed to the increasing popularity of cosmetic procedures, namely, higher availability, better affordability, and wider social acceptance over time. (SKINmed. 2022;20:422-427).

Treatments for Non-Syndromic Inherited Ichthyosis, Including Emergent Pathogenesis-Related Therapy.

The term 'inherited ichthyosis' refers to a heterogeneous group of mendelian disorders of cornification that involve the integument with varying degrees of scaling. The management of ichthyosis poses a challenge for most physicians. Treatment options proposed in the literature include moisturizers, topical keratolytics, topical and systemic vitamin D analogues, and topical and systemic retinoids; however, some of these modalities are less reliable than others. Despite the therapeutic impasse imposed by the options above, the emergence of pathogenesis-based treatments along with novel gene therapies appear promising and hold the potential to halt or even revert disorders that arise from single genetic mutations, although research is still quite lacking in this domain. Hence, this review aims to highlight the various treatment modalities available for the management of the cutaneous manifestations of non-syndromic inherited ichthyosis, with an added emphasis on pathogenesis-targeted therapies.

A Piez-o the jigsaw: the Piezo1 channel in skin biology.

The skin is the largest organ covering the entirety of the body. Its role as a physical barrier to the outside world as well as its endocrinological and immunological functions subject it to continuous internal and external mechanical forces. Thus, mechanotransduction is of the utmost importance for the skin in order to process and leverage mechanical input for its various functions. Piezo1 is a mechanosensitive ion channel that is a primary mediator of mechanotransduction and is highly expressed in the skin. The discovery of Piezo1 earned a Nobel Prize, and has had a profound impact on our understanding of physiology and pathology including paramount contributions in cutaneous biology. This review provides insight into the roles of Piezo1 in the development, physiology and pathology of the skin with a special emphasis on the molecular pathways through which it instigates these various roles. In epidermal homeostasis, Piezo1 mediates cell extrusion in conditions of overcrowding and division in conditions of low cellular density. Piezo1 also aids in orchestrating mechanosensation, DNA protection from mechanical stress and the various components of wound healing. Conversely, Piezo1 is pathologically implicated in melanoma progression, wound healing delay, cutaneous scarring and hair loss. By shedding light on these functions, we aim to unravel the potential diagnostic and therapeutic value Piezo1 might hold in the field of Dermatology.

The communicative paradigm shift of the digital age: The skinny on social media.

In this editorial, we explore several relevant issues pertaining to social media use including influencers and photo-editing software. The aforementioned topics are discussed vis-à-vis their profound positive and negative effects on both patients and aesthetic physicians. The reader is invited to appreciate the importance of social media use in aesthetic medicine and the pitfalls its use presents.

Genodermatoses with behavioural sequelae.

Children with genodermatoses are at an increased risk of developing behavioural disorders which may impart lasting damage on the individual and their family members. As such, early recognition of childhood mental health disorders via meticulous history taking, thorough physical examination, and disorder-specific testing is of paramount importance for timely and effective intervention. If carried out properly, prompt psychiatric screening and intervention can effectively mitigate, prevent or even reverse, the psychiatric sequela in question. To that end, this review aims to inform the concerned physician of the manifestations and treatment strategies relevant to the psychological sequelae of genodermatoses.

Genodermatoses with hearing impairment.

Hearing loss is a prominent feature in multiple genodermatoses. Underappreciation of auditory deficits can misdirect proper diagnosis by the treating dermatologist. This review reviews the anatomic, developmental, and embryologic aspects that characterize the ear and summarizes genodermatoses that have aberrant auditory findings. The latter are classified into neural crest, metabolic, pigmentary, craniofacial, and a miscellaneous category of disorders lacking specific cutaneous findings. The algorithms provided in this review enable treating dermatologists to better recognize and manage genodermatoses with ear involvement.

Characterizing the presence of neutrophil extracellular traps in neutrophilic dermatoses.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.

Comparative characterization of sun exposed and sun protected skin-derived mesenchymal-like stem cells in variegate porphyria and healthy individuals.

BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual. METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients. RESULTS: Results showed that the percentage of CD105+ cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient. CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.

Integrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal.

The beginning of the 21st century has been marked by three distinct waves of zoonotic coronavirus outbreaks into the human population. The COVID-19 (coronavirus disease 2019) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emerged as a global threat endangering the livelihoods of millions worldwide. Currently, and despite collaborative efforts, diverse therapeutic strategies from ongoing clinical trials are still debated. To address the need for such an immediate call of action, we leveraged the largest dataset of drug-induced transcriptomic perturbations, public SARS-CoV-2 transcriptomic datasets, and expression profiles from normal lung transcriptomes. Most importantly, our unbiased systems biology approach prioritized more than 50 repurposable drug candidates (e.g., corticosteroids, Janus kinase and Bruton kinase inhibitors). Further clinical investigation of these FDA-approved candidates as monotherapy or in combination with an antiviral regimen (e.g., remdesivir) could lead to promising outcomes in patients with COVID-19.

SuPAR, a potential inflammatory mediator in psoriasis pathogenesis.

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild-moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.