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Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

BACKGROUND/OBJECTIVES: The primary objective was to assess pain catastrophizing and functional disability in pediatric patients with epidermolysis bullosa (EB) and their parents/guardians. Secondary objectives included examining relationships between pain catastrophizing, functional disability, and correlations with other factors (e.g., age, disease severity, and percent of body surface area (BSA) involved). METHODS: Patients with EB ages 8-16 and their parents/guardians who were English or Spanish speaking completed a one-time online survey. Parent measures included: demographics questionnaire, Pain Catastrophizing Scale-Parent (PCS), and Parent Functional Disability Inventory (FDI). Child measures included: PCS child and child FDI. Higher scores on both scales indicate higher levels of catastrophizing and functional disability. RESULTS: Of 31 children, the mean age was 11.47 years and the majority (70.97%) had dystrophic EB. Mean scores were: 35.84 = PCS parent; 34.58 = PCS child; 30.87 = parent FDI; 29.77 = child FDI. Total scores for PCS parent, parent FDI, and child FDI increased significantly with disease severity and percentage of involved BSA (p

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

Prototheca wickerhamii is a rare cause of cutaneous and systemic infection that requires long treatment courses with potentially toxic medications. We describe a patient with cutaneous protothecosis refractory to triazole monotherapy who experienced clinical and radiographic improvement with the novel oral lipid nanocrystal formulation of amphotericin B without experiencing toxicity. [ABSTRACT FROM AUTHOR]

Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67–533.70]) or NTM (HR, 29.09 [95% CI, 9.51–88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29–114.80]) but not in patients with VZV (OR, 0.89 [95% CI,.30–2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P <.01) and VZV (IR, 0.006 vs 0 per person-day, P =.04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective. [ABSTRACT FROM AUTHOR]

Unwanted hair is a common concern among patients presenting to pediatric dermatology clinics, and parents and patients alike inquire about the safety of methods employed for elective removal. Various methods of hair removal exist with different levels of invasiveness and permanence, from simple mechanical depilation to light‐based therapies. All methods of hair removal appear to be safe and generally well tolerated in children, and there are no age restrictions to any modality. In this review, we aim to address the available literature on the safety and efficacy of hair removal modalities in pediatric patients and propose guidance on how to manage requests for at‐home and in‐office therapies within an ethical framework. [ABSTRACT FROM AUTHOR]

Objective: To describe a 41‐year‐old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin‐1 receptor antagonist (IL‐1Ra) protein, anakinra, since the age of 28, who presented with golf‐ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation. Methods: Clinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo‐red staining and proteomic evaluation of microdissected Congo red–positive amyloid deposits by liquid chromatography‐tandem mass spectrometry. Results: The skin, stomach, and kidney biopsies all showed the presence of Congo red–positive amyloid deposits. Mass spectrometry‐based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL‐1Ra protein)‐type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P‐component) and the amyloidogenic IL‐1Ra protein, which were present in Congo red–positive areas and absent in Congo red–negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL‐1Ra (anakinra) and not endogenous wild‐type IL‐1Ra. Conclusion: This is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra). [ABSTRACT FROM AUTHOR]

Background: Physical activity is associated with greater odds of sunburn in adults, increasing harmful sun exposure and skin cancer risk. The authors sought to investigate parallel associations between sunburn and physical activity among US high school students. Methods: The authors examined pooled cross-sectional data from the 2015 and 2017 Youth Risk Behavior Survey. A nationally representative sample of 21,894 US high school students who responded to the sunburn question was included. Results: Prevalence of sunburn was 56.6% between 2015 and 2017. Sunburn prevalence was higher in physically active students (88.3%; 95% confidence interval [CI], 86.7%–90.0%; P <.0001) and student athletes (63.0%; 95% CI, 59.4%–66.7%; P <.0001). Among male students who were vigorously physically active (≥5 d) or on ≥3 teams, the odds of sunburn were 2.33 (95% CI, 1.81–3.00; P <.0001) and 2.52 (95% CI, 1.96–3.23; P <.0001), respectively. Among female students who were vigorously physically active (≥5 d) or on ≥3 teams, the odds of sunburn were 1.65 (95% CI, 1.36–2.02; P <.0001) and 2.92 (95% CI, 2.07–4.13; P <.0001), respectively. Conclusions: Many US high school students are affected by sunburn, and the odds of sunburn are elevated during physical activity and team sports participation. Efforts are needed to improve sun safety regulations, education, and resources for youth during school and physical activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A review of global epidemiology data for alopecia areata (AA) highlights the need for improved and inclusive prevalence and incidence data. The study found that new therapies are effective in some patients, suggesting an incomplete understanding of the disease. The review also identified gaps in current AA epidemiology, with limited data available from only 28 out of 189 countries. The study emphasizes the importance of developing specific diagnostic codes for AA, distinguishing between different types of AA, and gathering more information about comorbidities and social determinants of health. Efforts can be borrowed from other diseases, such as atopic dermatitis, to address these gaps and improve understanding and care for AA patients. [Extracted from the article]

Background Emollients and keratolytics are frequently used to manage symptoms of congenital ichthyosis (CI). Systemic retinoid treatment is complicated by teratogenicity and dose-limiting adverse effects. Objectives This analysis from the randomized Phase IIb CONTROL study investigated the characteristics of participants who responded to treatment with TMB-001, a novel topical isotretinoin ointment formulation. Methods Participants ≥ 9 years of age with genetically confirmed CI and ≥ 2 (out of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%, TMB-001 0.1% or vehicle, twice daily for 12 weeks. Efficacy endpoints included the proportion of participants with ≥ 50% reduction in VIIS-scaling (VIIS-50) compared with baseline and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score compared with baseline. Changes in body surface area (BSA) involvement, Dermatology Life Quality Index (DLQI) scores and Itch-Numeric Rating Scale (I-NRS) scores were assessed. Results Among the 33 participants (11 randomized to TMB-001 0.05%, 10 to TMB-001 0.1% and 12 to vehicle), median age was 29 years (range 9–80), and most were male (64%) and White (79%). Baseline demographics were generally similar among participants who did or did not achieve TMB-001 treatment success. Participants who had lower mean BSA involvement and higher DLQI and I-NRS scores at baseline were more likely to achieve VIIS-50. Similarly, higher baseline DLQI and I-NRS scores were associated with IGA response; BSA involvement was similar for IGA responders vs. nonresponders. Conclusions Higher DLQI and I-NRS scores at baseline were associated with participants achieving treatment success by VIIS-50 and IGA response. Lower BSA involvement was associated with VIIS-50 success. [ABSTRACT FROM AUTHOR]

Background In two severe congenital ichthyosis subtypes, autosomal recessive lamellar ichthyosis (ARCI-LI) and X-linked recessive ichthyosis (XLRI), cutaneous manifestations include widespread scaling. Approved topical treatment options are limited to emollients and keratolytics. Aim This analysis from the randomized phase IIb CONTROL study assessed whether the efficacy and safety of TMB-001, a novel topical isotretinoin ointment formulation, differed between ARCI-LI and XLRI subtypes. Methods Participants ≥ 9 years with genetically confirmed XLRI or ARCI-LI and ≥ 2 (of 4) Visual Index for Ichthyosis Severity (VIIS) assessment areas with ≥ 3 scaling score were randomized 1 : 1 : 1 to TMB-001 0.05%/TMB-001 0.1%/vehicle, twice daily for 12 weeks. The proportion of participants with ≥ 50% reduction vs. baseline in VIIS scaling (VIIS 50; primary endpoint) and ≥ 2-grade reduction in Investigator's Global Assessment (IGA)-scaling score vs. baseline (key secondary endpoint) were evaluated. Adverse events (AEs) were monitored. Results Among enrolled participants (TMB-001 0.05%, n = 11; 0.1%, n = 10; and vehicle, n = 12), 52% had ARCI-LI and 48% XLRI subtypes. Mean age was 33.6 and 35.4 years for participants with ARCI-LI and XLRI, respectively. Overall, 33%, 50% and 17% of participants with ARCI-LI and 100%, 33% and 75% of participants with XLRI achieved VIIS 50 in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.24 for 0.05% vs. vehicle, intent-to-treat population). Improvement of ≥ 2-grade IGA score was observed in 33%, 50% and 0% of participants with ARCI-LI and 83%, 33% and 25% of participants with XLRI in the TMB-001 0.05%, TMB-001 0.1% and vehicle groups, respectively (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population). Most AEs were application-site reactions. Conclusion Regardless of congenital ichthyosis subtype, TMB-001 demonstrated greater proportions of participants achieving VIIS 50 and ≥ 2-grade IGA improvement vs. vehicle. [ABSTRACT FROM AUTHOR]

The 10th Pediatric Dermatology Research Alliance (PeDRA) Annual Conference occurred November 3–5, 2022 in Bethesda, Maryland. This conference was the first in‐person PeDRA conference after 2 years of a virtual format due to COVID‐19. Fittingly, given the effects of the pandemic, the conference theme was "Reimagining Community." The conference included presentations and panel sessions on finding individual and collective purpose, leveraging community in pursuit of a shared goal, and creating a community of resources in collaboration with NIH. The goal of this meeting was to connect clinicians, basic scientists, patients, patient advocates, and industry partners. The reimagined community of pediatric dermatology research is a synergistic space for all members to better understand, prevent, treat, and cure dermatologic diseases and conditions in children. This two‐and‐a‐half‐day conference with over 300 attendees featured educational seminars including a keynote address, didactic lecture and panel sessions, skill‐building workshops, 13 topic‐specific breakout sessions, and an interactive poster session where 108 active and finished research projects could be discussed. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) is an inherited disorder of immunity which leads to increased risk for mucocutaneous candidiasis and multiorgan autoimmune disease. While alopecia areata (AA) has been described in some patients with APECED, the extent and timing of AA is not well established and extent and timing of concomitant vitiligo and hypothyroidism has not been described. We evaluated an APECED cohort followed at the National Institutes of Health for the timing of development of associated diseases. We found AA occurred earlier in those with APECED than in the general population, was rarely the first sign of APECED, and the timing of AA onset did correlate with the timing of onset of vitiligo or hypothyroidism which also occurred at high rates and early age. [ABSTRACT FROM AUTHOR]