Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

The Role of Sex and Gender in Dermatology - From Pathogenesis to Clinical Implications.

BACKGROUND: Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress. OBJECTIVES AND PROJECT DESCRIPTION: The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth. FUTURE IMPACT: With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.

Skin disorders and interstitial lung disease: Part II-The spectrum of cutaneous diseases with lung disease association.

Part 2 of this 2-part CME introduces dermatologists to noninfectious inflammatory skin diseases associated with pulmonary involvement. In many cases, dermatologists may be the first physicians recognizing respiratory complications associated with these diagnoses. Because pulmonary involvement is often the leading cause of morbidity and mortality, dermatologists should be comfortable screening and monitoring for lung disease in high-risk patients, recognizing cutaneous stigmata of lung disease in these patients and referring to pulmonary specialists, when appropriate, for prompt treatment initiation. Some treatments used for skin disease may not be appropriate in the context of lung disease and hence, choosing a holistic approach is important. Interstitial lung disease and pulmonary hypertension are the most common pulmonary complications and a significant cause of mortality in autoimmune connective tissue diseases, especially systemic sclerosis, dermatomyositis, and mixed connective tissue disease. Pulmonary complications, notably interstitial lung disease, are also common and life-threatening in sarcoidosis and vasculitis, while they are variable in neutrophilic and autoimmune blistering diseases.

Exposure to silica and systemic sclerosis: A retrospective cohort study based on the Canadian Scleroderma Research Group.

Introduction: Systemic sclerosis (SSc) is thought to be induced by an environmental trigger in genetically predisposed individuals. This study assessed the demographic and clinical characteristics and disease severity of silica exposed SSc patients. Methods: Data was obtained from the Canadian Scleroderma Research Group (CSRG) cohort, containing 1,439 patients (2004-2019). Univariate and multivariate logistic regression analyses were performed, to determine the phenotype and severity of silica-exposed SSc patients. Mortality was assessed using Cox Survival Regression and Kaplan-Meier analyses. Results: Among 1,439 patients (86.7% females), 95 patients reported exposure to silica. Those exposed were younger, of male sex and with more severe disease. Sex differences were observed where male patients exposed to silica were more likely to be Caucasian and smokers whereas female patients were younger at SSc diagnosis compared to unexposed. Multivariate regression, controlled for multiple confounders, showed that silica exposure was associated with a younger age at diagnosis and worse disease severity and mortality. Conclusion: Exposure to silica was reported in ∼7% of CSRG cohort and ∼20% of male patients and was associated with a worse prognosis in terms of age of diagnosis, organ involvement and mortality. Hence, screening for silica exposure among higher risk individuals may be beneficial and these patients may require closer monitoring for systemic disease.

Omalizumab for the Treatment of Bullous Pemphigoid: A Systematic Review of Efficacy and Safety.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease. Current treatment strategies are limited by their efficacy and/or side effect profile and the need for safer and effective alternatives is undeniable. We aimed to conduct a systematic review focusing on the efficacy and safety of omalizumab in BP patients. Embase, PubMed, Cochrane, and clinicaltrials.gov were searched for English and French articles published from inception to July 1, 2021, using search terms "omalizumab" OR "Xolair" OR "IGE025" OR "olizumab" AND "bullous pemphigoid." Screening and data extraction was performed by two raters independently. The primary outcome was complete response (CR), and secondary outcomes were partial response (PR), flare-ups, adverse events/vital status. In total, 22 articles were included, with a total of 56 patients. All patients had a refractory BP with mean disease duration of 13.5 ± 20.2 months (Standard Deviation (SD)) and failed 3.1 ± 1.6 therapies and many remained corticosteroids dependent. Overall, 87.5% of patients responded to treatment (55.4% CR and 32.1% PR), 7.1% discontinued the protocol and only 5.4% were non responders. A third of patients were able to discontinue all other therapies and most others were able to discontinue or taper systemic corticosteroids to <10 mg daily. Flare-ups occurred in 57.7% of patients upon discontinuation of omalizumab and/or steroid tapering, most patients recaptured response thereafter. Omalizumab was well tolerated by most patients. Omalizumab appears to be a promising treatment for BP with a good response rate and safety profile. However, several limitations were identified in current literature, and highlight the need for randomized controlled trials of omalizumab in BP.

Adult-onset en coup de sabre scleroderma in a patient with linear localized scleroderma profunda: A case report and literature review.

The en coup de sabre variant of linear scleroderma typically occurs in children. We report a unique case of adult-onset en coup de sabre scleroderma in a patient with linear localized scleroderma profunda. The patient was treated with oral steroids and oral methotrexate improving her cutaneous disease. This case highlights the importance of a thorough cutaneous examination as this adult patient developed an entity traditionally believed to occur in childhood.

Saccadic adaptation in the presence of artificial central scotomas.

Saccadic adaptation can occur over a short period of time through a constant adjustment of the saccade target during the saccade, resulting in saccadic re-referencing, which directs the saccade to a location different from the target that elicited the saccade. Saccade re-referencing could be used to help patients with age-related macular degeneration to optimally use their residual visual function. However, it remains unknown whether saccade adaptation can take place in the presence of central scotomas (i.e., without central vision). We tested participants in two experiments in a conventional double-step paradigm with a central gaze-contingent artificial scotoma. Experiment 1 (N = 12) comprised a backward adaptation paradigm with no scotoma control, visible, and invisible 3° diameter scotoma conditions. Experiment 2 (N = 13) comprised a forward adaptation paradigm with no scotoma control, invisible 2°, and 4° diameter scotoma conditions. In Experiment 1, we observed significant adaptation in both the visible and invisible scotoma conditions comparable to the control condition with no scotoma. This was the case even when the saccade landed such that the target was occluded by the scotoma. We observed that adaptation occurred based on peripheral viewing of the stepped target during the deceleration period. In Experiment 2, we found that both scotoma conditions showed adaptation again comparable to the control condition with no scotoma. We conclude that saccadic adaptation can occur with central scotomas, showing that it does not require central vision and can be driven primarily by peripheral retinal error.

Toward Understanding of Environmental Risk Factors in Systemic Sclerosis [Formula: see text].

IMPORTANCE: Systemic sclerosis (SSc) is a severe, chronic, and incurable autoimmune fibrotic skin disease with significant extracutaneous involvement. Low concordance rate in twin studies and unequal geographic distribution of SSc argues for importance of environment in disease initiation and progression. OBJECTIVE: In this manuscript we provide a summary of all investigated potential external risk factors for SSc. DATA SOURCES: A literature search in PubMed and EMBASE database was performed for studies published until January 1, 2020 by 2 reviewers (EN and LO) independently. FINDINGS: Occupational and/or environmental exposures to silica and organic solvents are associated with increased incidence and severity of SSc. Exposure to epoxy resins, asbestos, and particulate air pollution favors increased risk of SSc, but data are based on limited number of observational studies. There is insufficient evidence to conclude an association between SSc development and other occupational (eg, welding fumes) or personal exposures (eg, smoking, vitamin D deficiency). Association of SSc with silicone breast implants has been disproven. Infectious pathogens (eg, Helicobacter pylori and angiotropic viruses) and dysbiosis seem to play a role in SSc development and severity, but their role remains to be clarified. CONCLUSIONS AND RELEVANCE: It may be prudent to counsel our patients with SSc (or those at risk of SSc) to avoid occupations with exposure to silica, organic solvents, asbestos and epoxy resins; restraint from smoking, using cocaine or drugs with pro-fibrotic potential. While the association between low vitamin D and SSc remains to be confirmed, we believe that SSc patients should be encouraged to maintain healthy vitamin D levels as benefits outweigh the risks.