SpatialView: an interactive web application for visualization of multiple samples in spatial transcriptomics experiments.

MOTIVATION: Spatial transcriptomics (ST) experiments provide spatially localized measurements of genome-wide gene expression allowing for an unprecedented opportunity to investigate cellular heterogeneity and organization within a tissue. Statistical and computational frameworks exist that implement robust methods for pre-processing and analyzing data in ST experiments. However, the lack of an interactive suite of tools for visualizing ST data and results currently limits the full potential of ST experiments. RESULTS: To fill the gap, we developed SpatialView, an open-source web browser-based interactive application for visualizing data and results from multiple 10× Genomics Visium ST experiments. We anticipate SpatialView will be useful to a broad array of clinical and basic science investigators utilizing ST to study disease. AVAILABILITY AND IMPLEMENTATION: SpatialView is available at https://github.com/kendziorski-lab/SpatialView (and https://doi.org/10.5281/zenodo.10223907); a demo application is available at https://www.biostat.wisc.edu/˜kendzior/spatialviewdemo/.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

Pernio and early SARS-CoV-2 variants: natural history of a prospective cohort and the role of interferon.

Cases of new-onset pernio and recurrences in our cohort align tightly with trends in mean 7-day COVID-19 positivity in Wisconsin and mean temperature in Madison, Wisconsin by month.

Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

Clearance of atypical cutaneous manifestations of hyper-IgE syndrome with dupilumab.

Hyper-IgE syndromes (HIES) are a heterogeneous group of rare primary immunodeficiency diseases classically characterized by the triad of atopic dermatitis, and recurrent cutaneous and pulmonary infections. Autosomal dominant, loss-of-function STAT3 pathogenic variants are the most common genetic cause, which lead to deficiency of Th17 lymphocytes, impaired interferon gamma production, and IL-10 signal transduction, and an unbalanced IL-4 state. Dupilumab, a monoclonal antibody to the IL-4a receptor, inhibits both IL-4 and IL-13, and has been shown to improve atopic dermatitis and other manifestations of HIES including asthma and allergic bronchopulmonary aspergillosis. We present a pediatric patient with HIES who presented predominantly with eosinophilic folliculitis, recurrent cutaneous infections, and other non-eczematous findings and achieved sustained clearance with dupilumab.

Early-onset hypertension associated with extensive cutaneous capillary malformations harboring postzygotic variants in GNAQ and GNA11.

BACKGROUND AND OBJECTIVES: Cutaneous capillary malformations (CMs) describe a group of vascular birthmarks with heterogeneous presentations. CMs may present as an isolated finding or with other associations, including glaucoma and leptomeningeal angiomatosis (i.e., Sturge-Weber syndrome) or pigmentary birthmarks (i.e., phakomatosis pigmentovascularis). The use of targeted genetic sequencing has revealed that postzygotic somatic variations in GNAQ and GNA11 at codon 183 are associated with CMs. We report five patients with early-onset hypertension and discuss possible pathogenesis of hypertension. METHODS: Twenty-nine patients with CMs, confirmed GNAQ/11 postzygotic variants, and documented past medical history were identified from a multi-institutional vascular anomalies study. Early-onset hypertension was defined as hypertension before the age of 55 years. Clinical data were reviewed for evidence of hypertension, such as documentation of diagnosis or elevated blood pressure measurements. RESULTS: Five of the 29 patients identified as having GNAQ/11 postzygotic variants had documented early-onset hypertension. Three individuals harbored a GNAQ p.R183Q variant, and two individuals harbored a GNA11 p.R183C variant. All individuals had extensive cutaneous CMs involving the trunk and covering 9%-56% of their body surface area. The median age of hypertension diagnosis was 15 years (range 11-24 years), with three individuals having renal abnormalities on imaging. CONCLUSIONS: Early-onset hypertension is associated with extensive CMs harboring somatic variations in GNAQ/11. Here, we expand on the GNAQ/11 phenotype and hypothesize potential mechanisms driving hypertension. We recommend serial blood pressure measurements in patients with extensive CMs on the trunk and extremities to screen for early-onset hypertension.

Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants.

Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo-cranio-cutaneous lipomatosis, and Schimmelpenning-Feuerstein-Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T-cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS-related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings.

Light-based treatment of pediatric port-wine birthmarks.

Port-wine birthmarks (PWBs) are progressive vascular malformations with significant disfigurement and psychosocial morbidity; early light-based treatment has shown improved outcomes in the pediatric population. Somatic mosaic mutations underly the progressive nature of PWBs and explain the significant differences in response and heterogeneity of vessel architecture in the pediatric population when compared to the adult cohort. Here, we summarize a review of pediatric specific literature on the various light-based treatment modalities, including pulsed dye laser, near-infrared lasers, and intense pulsed light, providing the various indications, tips, advantages, and disadvantages for the pediatric dermatologist.

Clearance of pediatric actinic prurigo with dupilumab.

Actinic prurigo is a rare, idiopathic chronic photodermatosis of childhood characterized by excoriated papules, nodules, and plaques in sun-exposed areas. It is notoriously difficult to treat. The disorder involves a type IV hypersensitivity reaction driven by both Th1 and Th2 inflammatory pathways, the latter of which leads to secretion of IL-4, IL-5, IL-13, and production of B cells, IgE, and IgG4. Dupilumab, an IL-4 receptor antagonist, disrupts the Th2 pathway. We present a pediatric patient with severe, recalcitrant actinic prurigo who achieved rapid and sustained clearance with dupilumab.

Lipoatrophic panniculitis in an adolescent.

Lipoatrophic panniculitis (LP) is a rare childhood panniculitis characterized by sclerotic, atrophic plaques on the extremities. We present a case of LP diagnosed during the inflammatory phase that was difficult to distinguish clinically from eosinophilic fasciitis. This report adds to the limited phenotypic spectrum of LP by differentiating the clinical features of disease activity from disease damage and highlighting the importance of biopsy in establishing a diagnosis.

Hypergammaglobulinemic purpura of Waldenström in children.

BACKGROUND: Hypergammaglobulinemic purpura of Waldenström (HGPW), a rare cutaneous eruption characterized by the triad of recurrent episodes of lower extremity petechiae, symptoms of stinging and burning, and lower extremity edema, is poorly described in children. Some children have been reported to follow a benign course, while others are eventually diagnosed with fulminant rheumatologic disease. OBJECTIVES: To determine the distinguishing features of HGPW including the spectrum of disease manifestations and clinical outcomes. METHODS: This is a multicenter, retrospective case series of six children with HGPW combined with a literature review of 45 previously published pediatric cases. RESULTS: Most children were eventually diagnosed with systemic disease (63%) or developed autoantibody accumulation suggestive of evolving disease (71%). The most common diagnoses were Sjogren's syndrome and systemic lupus erythematosus. The mean duration between onset of cutaneous eruption and diagnosis of systemic disease was 5.6 years, underscoring that HPGW patients often present with a rash that precedes the development of systemic symptoms. CONCLUSIONS: Diagnosis of HGPW should prompt initial screening for rheumatologic disease with long-term rheumatology follow-up, as the majority of patients present with evolving manifestations of systemic disease.

Clinical and histologic presentation of pediatric reactive granulomatous dermatitis.

OBJECTIVE: To characterize the clinical and histologic presentation of reactive granulomatous dermatitis (RGD) in the pediatric population. METHODS: In this multicenter retrospective chart review, 7 pediatric patients with biopsy-proven RGD were identified. Photographs, histology reports, and clinical course were reviewed to discover patterns in demographics, comorbid conditions, autoimmune sequelae, drug exposures, infections, morphology, and histologic features. RESULTS: Overall, 7 patients were included and analyzed. Most were female and Hispanic. All presented with a similar dermatologic phenotype previously described in the adult literature including macular erythema and annular, pink to violaceous, edematous papules and plaques, often involving proximal extremities and extensor joints. All biopsies demonstrated variable collagen alteration and a perivascular interstitial infiltrate of histiocytes with or without mucin. Neutrophils or karyorrhexic debris were present in 4/7 of the biopsies, and eosinophils were occasionally seen (2/7 cases). In all cases, RGD was associated with active SLE or led to a new diagnosis, and initiation of systemic treatment improved cutaneous disease. CONCLUSIONS: Pediatric RGD was more common in female patients and ethnic minorities, and strongly associated with SLE. Clinical and histologic presentations were consistent across all cases with only minor variations, suggesting that recognition and confirmation might be expedited by familiarity with these dominant patterns. Diagnosis of RGD in pediatric patients should prompt screening for SLE.

Cutaneous manifestations of pediatric lupus.

PURPOSE OF REVIEW: To review recent evidence on cutaneous manifestations of lupus, with a focus on evidence for pediatric patients. RECENT FINDINGS: Cutaneous manifestations of SLE are common and may precede signs or symptoms of systemic disease. Early recognition and initiation of therapy improves quality of life by reducing cutaneous disease activity. Antimalarials are first line for moderate-to-severe disease. Photo protection is a critical component of therapy and perhaps the only modifiable risk factor for SLE. Recognition of cutaneous vasculopathy may reduce mortality from vascular occlusion. SUMMARY: There is a critical need for better understanding of pathogenesis, risk factors and outcomes in cutaneous lupus to determine optimal treatment and surveillance strategies. Correlation of clinical phenotypes with biomarkers may help to stratify patients, optimize targeted interventions, and influence prognosis.

Increasing Access to High Value Care: Preventing Complications in Common Disorders.

Most infantile hemangiomas (IHs), the most common vascular tumors of childhood, evolve without complications; however 10% to 12% require specialty referral for treatment. To emphasize the complications of late referral, we present a case of necrotizing infection within a segmental IH leading to sepsis. Early evaluation by a pediatric dermatologist could have prevented this life-threatening and disfiguring complication. We discuss how teledermatology would enable rapid triage of such critical cases in underserved areas, increasing access to high-value care and optimizing outcomes for our most vulnerable patients.

Immunogenetics of cutaneous lupus erythematosus.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is the prototypic autoimmune condition, often affecting multiple organ systems, including the skin. Cutaneous lupus erythematosus (CLE) is distinct from SLE and may be skin limited or associated with systemic disease. Histopathologically, the hallmark of lupus-specific manifestations of SLE and CLE is an interface dermatitis. The cause of SLE and CLE is likely multifactorial and may include shared genetic factors. In this review, we will discuss the genetic findings related to the cutaneous manifestations of SLE and isolated CLE, with a particular focus on the lupus-specific CLE subtypes. RECENT FINDINGS: Several major histocompatibility complex and nonmajor histocompatibility complex genetic polymorphisms have been identified which may contribute to the cutaneous manifestations of SLE and to CLE. Most of these genetic variants are associated with mechanisms attributed to the pathogenesis of SLE, including pathways involved in interferon and vitamin D regulation and ultraviolet light exposure. Although there is overlap between the genetic factors associated with SLE and CLE, there appear to be unique genetic factors specific for CLE. SUMMARY: Improved understanding of the genetics of CLE may lead to the creation of targeted therapies, improving outcomes for patients with this challenging dermatologic condition.

Iatrogenic Necrolytic Migratory Erythema in an Infant with Congenital Hyperinsulinism.

Necrolytic migratory erythema (NME) is a rare cutaneous finding characterized by painful, pruritic, scaly red patches and plaques, bullae, and superficial erosions. Typically NME is a paraneoplastic phenomenon associated with glucagonoma. We report the exceptional case of an infant who developed iatrogenic NME arising secondary to glucagon therapy for congenital hyperinsulinism.