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Sweet syndrome is a neutrophilic dermatosis characterized by an autoinflammatory nature and a sterile neutrophilic infiltrate. It presents with tender, erythematous, edematous papules or plaques, often accompanied by fever. Aim of this review is to summarize the most meaningful aspects of Sweet syndrome, critically discussing old paradigms and novel findings. A search of the English-language literature was conducted using the terms "Sweet syndrome" and "acute febrile neutrophilic dermatosis." MEDLINE (via PubMed) and Web of Science (WOS) databases were consulted up to June 30, 2024. Since its first identification, new clinical and histopathological variants of Sweet syndrome have been described, highlighting its heterogeneity. Additionally, a multitude of clinical conditions have been increasingly reported in association with Sweet syndrome, ranging from malignancies, autoimmune and infectious disorders. The pathogenesis of the disease is unclear and varies according to the associated conditions. One unifying mechanism is the aberrant activation, proliferation, and skin homing of neutrophils. The mainstay of treatment remains systemic corticosteroids; alternatives include colchicine, dapsone, and potassium iodide. Traditional immunosuppressants, biologic agents, and small molecules have also been described as effective in treating Sweet syndrome. Sweet syndrome is a heterogeneous condition with an elusive pathogenesis. Most cases resolve with corticosteroids, but some remain refractory to various therapies, representing an unmet medical need. Recent evidence on the pathomechanisms underlying Sweet syndrome suggests that not only innate but also adaptive immunity might play roles. Further experimental studies are needed and may help identify new therapeutic targets in the future.

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue 1-3 . Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN 4-6 . Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics 7,8 . We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy., (© 2024. The Author(s).)

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but can cause immune-related adverse events (irAEs). Severe cutaneous irAEs, including epidermal necrolysis, are rare but potentially life-threatening. There is limited understanding of the clinical features and management of ICI-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), so we aimed to analyze 95 cases of ICI-induced SJS/TEN (35 cases of SJS, 26 cases of TEN, two cases of SJS/TEN overlap, and 32 cases of unspecified) to increase knowledge of this condition among oncologists and dermatologists. We conducted a comprehensive search of PubMed for all relevant case reports published until the end of December 2022, and collected data on patient demographics, cancer type, ICI regimen, time to onset of SJS/TEN, clinical presentation, management strategies, and outcomes. PD-1 inhibitors were the most common ICIs associated with SJS/TEN (58.9%), followed by the combination of PD-1 and CTLA-4 inhibitors (11.6%), and PD-L1 inhibitors (6.3%). Lung cancer and melanoma were the most frequent malignancies treated (35.8% and 25.4%, respectively). SJS/TEN occurred most frequently within the first 4 weeks (51.7%), and corticosteroid monotherapy was the most commonly chosen systemic treatment (56.4%). The overall mortality rate of ICI-induced SJS/TEN was 30.8%. Our findings highlight the frequency and severity of ICI-induced SJS/TEN and the urgent need for predictive molecular biomarkers aimed at preventive measures and early intervention., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1β, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1β, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1β in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1β. This study shows that IL-1β produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Defining the molecular phenotype of single cells in situ is key for understanding tissue architecture in health and disease. Advanced imaging platforms have recently been joined by spatial omics technologies, promising unparalleled insights into the molecular landscape of biological samples. Furthermore, high-precision laser microdissection (LMD) of tissue on membrane glass slides is a powerful method for spatial omics technologies and single-cell type spatial proteomics in particular. However, current histology protocols have not been compatible with glass membrane slides and LMD for automated staining platforms and routine histology procedures. This has prevented the combination of advanced staining procedures with LMD. In this study, we describe a novel method for handling glass membrane slides that enables automated eight-color multiplexed immunofluorescence staining and high-quality imaging followed by precise laser-guided extraction of single cells. The key advance is the glycerol-based modification of heat-induced epitope retrieval protocols, termed "G-HIER." We find that this altered antigen-retrieval solution prevents membrane distortion. Importantly, G-HIER is fully compatible with current antigen retrieval workflows and mass spectrometry-based proteomics and does not affect proteome depth or quality. To demonstrate the versatility of G-HIER for spatial proteomics, we apply the recently introduced deep visual proteomics technology to perform single-cell type analysis of adjacent suprabasal and basal keratinocytes of human skin. G-HIER overcomes previous incompatibility of standard and advanced staining protocols with membrane glass slides and enables robust integration with routine histology procedures, high-throughput multiplexed imaging, and sophisticated downstream spatial omics technologies., Competing Interests: Conflict of interest M. M. is an indirect investor in Evosep Biosciences. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cutaneous lichenoid drug eruptions (LDE) are adverse drug reactions (ADR) characterized by symmetric, erythematous, violaceous papules reminiscent but rarely fully characteristic of lichen planus (LP). We aimed to analyse the literature describing cases of LDE within the last 20 years to provide additional insight into culprit drugs, typical latency to onset of the eruption, the spectrum of clinical presentations, severity and management. A literature search was conducted in MEDLINE between January 2000 and 27 January 2021. The keywords 'lichenoid drug rash' and 'lichenoid drug eruption' were used. Cases were included if LDE diagnosis was made, and culprit drugs were identified. A total of 323 cases with LDE were identified from 163 published case reports and studies. The mean patient age was 58.5 years (1 month to 92 years), and 135 patients (41.8%) were female. Checkpoint inhibitors (CKI) were the most frequently reported culprit drugs (136 cases; 42.1%), followed by tyrosine kinase inhibitors (TKI) (39 cases; 12.0%) and anti-TNF-α-monoclonal antibodies (13 cases; 4.0%). The latency between initiation of the drug and manifestation was 15.7 weeks (range: 0.1-208 weeks). After discontinuing the culprit drug, the median time to resolution was 14.2 weeks (range: 0.71-416 weeks). One hundred thirty-six patients (42.1%) were treated with topical, and 54 patients (16.7%) with systemic glucocorticoids. Overall, we conclude that, albeit rare, LDE is challenging to diagnose ADR induced by mostly CKI, TKI, and biologics. Treatment modalities resemble that of lichen planus, and the culprit drugs had to be discontinued in only 26%, which is low compared with other types of adverse drug reactions. This is probably due to the low risk of aggravation (e.g. toxic epidermal necrolysis) if the drug is continued and the benefit/risk ratio favouring the drug, as is often the case in cancer therapy., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

While the incidence of infections with the human immunodeficiency virus largely remained unchanged in Germany, an increase of other sexually transmitted infections (STIs) was observed. The aim was to analyse the effectiveness of our sexual education lecture for students in improving the awareness, knowledge and prevention of STIs. We conducted a cross-sectional survey after students had attended our extra-curricular lecture at the Department of Dermatology of the Ludwig-Maximilians-University of Munich, Germany (LMU). We compared the data with a previously performed study in which the same survey was carried out before the lecture had started. A total of 5866 questionnaires were included in the analysis. After attending the lecture significantly more students were aware of STIs (syphilis: 36.8% (before) vs. 63.5% (after); chlamydia: 30.5% vs. 49.3%; gonorrhoea: 22.4% vs. 38.2%; human papillomaviruses (HPV): 17.7% vs. 30.2%), the transmission pathways of STIs (oral: 36.6% vs. 82.6%; vaginal: 81.8% vs. 97.3%; anal: 42.8% vs. 94.0%; penile: 68.7% vs. 92.1%), knew that the HPV vaccination is directed against a virus (36.8% vs. 56.9%) and were interested in receiving a vaccination (57.7% vs. 78.8%). This study demonstrates the positive educative effects of our lecture for awareness and improved knowledge of STIs. To satisfy the need for a comprehensive sexual education, a combination of school and health facility-based programmes should be implemented as one single lecture cannot convey the entire information about STIs.

Background: Acute generalized exanthematous pustulosis (AGEP) is a potentially severe adverse cutaneous drug reaction, which typically occurs within 24-48 h after the intake of the culprit drug., Summary: AGEP is characterized by numerous sterile subcorneal pustules on erythematous skin and in less than a third of cases it can be associated with organ manifestations possibly leading to life-threatening symptoms (e.g., cholestasis, nephritis, and lung and bone marrow involvement). In contrast to generalized pustular psoriasis, it can involve mucosal regions and typically resolves rapidly if the culprit drug is removed, and adequate therapy with topical or systemic steroids administered. Diagnosis based on patient history, clinical signs, and characteristic cutaneous histology is rarely challenging. Identification of the culprit drug may be aided by patch testing or lymphocyte transformation tests that are of limited value., Key Messages: Recent experimental data reviewed herein are supportive of an early role of drug-induced innate immune activation and innate cytokines such as interleukin (IL)-1, IL-36, and IL-17 in the pathogenesis of AGEP. This explains the rapid onset and neutrophilic character of the cutaneous inflammation, but also provides new avenues for in vitro tests aimed at better identifying the culprit drug., (© 2023 S. Karger AG, Basel.)

Introduction: The coronavirus pandemic forced universities to transfer academic curricula into the digital realm and calls for the introduction of new teaching methods to adequately compensate for the limited in-patient training. Especially in the field of dermatology, the use of 3D models presents an interesting opportunity to maintain the teaching of diagnostically essential sensory and haptic characteristics of primary lesions., Objectives: We developed a prototype silicone model and presented it to the medical service of the Department of Dermatology of the Ludwig-Maximilians University for evaluation., Methods: Silicone models demonstrating primary skin lesions were produced by using negative 3D-printed molds and different types of silicone. An online survey obtained evaluations from a group of dermatologists regarding the quality of previously supplied silicone 3D models and their potential use in medical education. Data from 58 dermatologists were collected and analyzed., Results: The majority of the participants rated the models overall as positive and innovative, providing constructive feedback for additional modifications, and recommended further implementation into the regular curriculum as an additional tool after the end of the pandemic., Conclusions: Our study underlined the possible advantages of using 3D models as a supplement in educational training even after the end of the SARS-CoV-2 pandemic.

Background: Demodex spp. mites are the most complex resident of the human skin microbiome. Although they are considered commensals, they can be pathophysiologically relevant in inflammatory skin diseases like rosacea. Until now, there is no culture system available for these mites except for using live vertebrate hosts., Objectives: Our aim was to establish an ex vivo culture of human Demodex mites and to characterize the sebogenesis-dependent mite density., Methods: Demodex mites were cultivated in pilosebaceous units of human skin explants, called human organotypic skin explant culture (hOSEC). Furthermore, different sebogenesis-modifying additives were evaluated. Mites and mite survival were evaluated using light and fluorescence microscopy., Results: After 90 days of incubation, living Demodex mites - including eggs, larvae and nymphs - were detected in the dissected skin samples. Incubation for 30 days with anabolic steroids (testosterone and trenbolone) as well as retinol and retinoic acid (isotretinoin) yielded a reduced mite density., Conclusions: With this technique, mites can be cultivated ex vivo for the first time, thereby establishing new ways to investigate Demodex spp. The sebostatic effect of isotretinoin might explain the mechanism of action in the off-label treatment of rosacea. We anticipate our findings to be the basis of an accelerated research on our most complex commensal, its life, biology and physiology., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Acne vulgaris is an inflammatory skin disorder leading to an impairment of quality of life and is therefore not only a cosmetic issue. Its pathogenesis is multifactorial - of particular importance is the colonization with the bacterium Propionibacterium acnes. A wide range of different treatment options exists including topical and systemic treatments depending on severity. High Frequency (HF) therapy, historically developed in the 19 th century, claims antimicrobial effects on acne skin, but solid data on its efficacy and mechanism of action is lacking., Objectives: The main objective of this study was to determine the efficacy of HF therapy on skin flora and P. acnes in vitro using a commercial device as well as to review studies on the mechanism of action., Methods: The plasma source was investigated regarding electrical settings, heat, and ozone development. Bacterial skin flora, fungal isolates, and P. acnes were exposed to HF in vitro and compared to unexposed controls by evaluating the number of colonies on agar plates. To further analyze bacterial species from normal skin flora, 16S-sequencing was performed. Statistical analyses were carried out using row analysis and unpaired t-test., Results: HF treatment led to a significant reduction of almost every bacterial and fungal species investigated in this study. Moreover, the number of colonies forming units was significantly decreased in P. acnes after HF treatment compared to controls in vitro., Study Limitations: The experiments were performed in vitro only. To assess clinical effects further in vivo experiments are necessary., Conclusions: The results collected in this study, although in vitro, provide a mechanistic basis for HF as a complementary treatment option for patients with acne. It might also have a beneficial effect on patients with superficial infectious skin of the skin., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: Allergic diseases represent a major global health issue with more than one-third of the global population affected by at least one allergic condition. Allergic conditions can not only cause life-threatening anaphylactic reactions but also impact daily life with a significant influence on mental health and the quality of life (QoL)., Objectives: This study aims to evaluate the health-related QoL and depression severity among patients presenting in a tertiary care allergy center., Methods: A cross-sectional study was conducted among 596 patients presenting with allergic symptoms or previously diagnosed allergies between October 2018 and April 2019.Patients were screened for depression and the QoL impairment by using three validated scales: the Beck Depression Inventory (BDI), the Dermatologic Life Quality Index (DLQI), and the three-level version of the EuroQol 5-Dimensional (EQ-5D-3L) scale., Results: One-third (34.8%) of the study population was male and two-thirds (65.2%) were female. About 73.7% (n = 427/579) of the patients suffered from at least one previously diagnosed allergic disease, most frequently to pollen (37.0%, n = 214/579) and food (27.3%, n = 158/579), and 20.0 % (n = 116/579) suffered from urticaria. About 19.3% of the total population suffered from depression. Urticaria, as well as insect venom, food/food additives, and drug allergies significantly affected the QoL and depression severity (p < 0.001), reflected by higher DLQI and BDI scores, and lower scores in the EQ5D-3L index., Conclusion: Our results provide evidence for a possible correlation of allergies (e.g. against insect venom, food/food additives, and drugs) and/or urticaria with a reduced QoL and a higher depression rate. Patients particularly indicated restrictions for the dimensions, pain/discomfort as well as anxiety/depression. It might be beneficial to implement a standardized questionnaire as a regular screening method for evaluating the mental health status of patients with allergies and/or urticaria., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: The corona pandemic affects many aspects of life - with challenges in medical treatment undoubtedly of paramount importance. However, continuing medical education needs to be consistently provided. During a semester with lockdown-phases and limited student-to-patient-contact availability, we supplied silicone models of primary skin lesions to every student and asked them to evaluate this teaching tool., Methods: In two anonymous online surveys, we asked students enrolled in dermatology (n = 222) at the Medical Facility of the Ludwig Maximilian University of Munich in the winter semester 2020/2021 - subsequent to online teaching - about their understanding and self-assessment of primary skin lesions before and after receiving silicone models for practice. The models were produced by layering different types of silicone into negative 3D printed molds made from polylactide to attain different degrees of hardness and colors., Results: Data from 211 (95.0 %) and 213 (95.9 %) of the 222 students were analyzed before and after receiving the silicone models, respectively. In all questions the students stated a highly significant improvement in their skills (P < 0.001). The majority of students evaluated the silicone models positively and reported a better understanding and learning of primary skin lesions., Conclusions: This study demonstrates the benefit of haptic experience in dermatology teaching not only in the time of COVID-19, but also thereafter., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Hintergrund und Ziele: Die Corona-Pandemie betrifft eine Fülle von verschiedenen Lebensaspekten - Herausforderungen in der medizinischen Behandlung sind hier unzweifelhaft von höchster Wichtigkeit. Allerdings muss auch, um die Ausbildung von Studierenden zu gewährleisten, fortlaufende medizinische Lehre stattfinden. Während eines Semesters mit Lockdown-Phasen und eingeschränktem Patientenkontakt für die Studierenden schickten wir jedem Studierenden ein Silikonmodell zu und baten um die Evaluation dieses Lernwerkzeugs. Methoden: Mittels zweier vollständig und irreversibel anonymisierter Online-Fragebögen befragten wir Studierende des Dermatologie-Semesters (n  =  222) an der Medizinischen Fakultät der Ludwig-Maximilians-Universität in München im Wintersemester 2020/2021 - anschließend an Online-Lehre - zu ihrem Verständnis und der Eigeneinschätzung zu Primäreffloreszenzen vor und nach Erhalt der Silikonübungsmodelle. Diese wurden durch Schichtung verschiedener Silikontypen in negative 3D-Polylactid-Formen hergestellt, um bestimmte Festigkeiten und Farben darzustellen. Ergebnisse: Insgesamt wurden Fragebögen von 211 (95,0 %) und 213 (95,9 %) der 222 Studierenden analysiert, jeweils vor und nach dem Erhalt der Silikonmodelle. Die Studierenden gaben eine statistisch signifikante Zunahme ihrer Fähigkeiten an (P < 0,001). Ein Großteil der Studierenden evaluierte die Silikonmodelle positiv und berichtete von einem besseren Verständnis und Lernen der Primäreffloreszenzen. Schlussfolgerungen: Diese Lehrstudie zeigt die Vorzüge der haptischen Erfahrung in der dermatologischen Lehre auf - nicht nur in Zeiten von COVID-19, sondern auch danach., (© 2022 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Introduction: In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome (SS), treated with the retinoid alitretinoin during a 7-year period at our outpatient department between 2015 and 2020., Materials and Methods: We analyzed patient medical records including TNMB stage, side effects under therapy with alitretinoin, time to next treatment (TTNT), and previous photo documentation., Results: A total of 35 patients with MF (n = 28) and SS (n = 7) were included in the study, of whom 69% were male and 31% were female. The mean age of onset was 56 ± 15 years in MF and 65.4 ± 10.8 years in SS with 51.4% having early stage (IA-IIA) and 48.6% having advanced stage (IIB-IVA) CTCL. Of these patients 37.2% responded to alitretinoin, 28.6% had a stable course, and 34.3% experienced progression. Alitretinoin was administered as a monotherapy (25.7%) or combined with five concomitant therapies (74.2%), most frequently with ECP (31.4%) and PUVA (11.4%). 63% did not report any side effects, most often hypertriglyceridemia (20%) was described., Conclusion: Considering that nearly two thirds of the CTCL patients treated with alitretinoin showed a response or stable disease, together with a low number of side effects and low cost compared to bexarotene, alitretinoin may be a potential alternative in the treatment of less advanced CTCLs. This survey represents the largest number of recorded therapies with the retinoid alitretinoin in CTCLs in a European patient collective., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Remote consultations are likely to grow in importance in the following years, especially if the coronavirus disease 2019 (COVID-19) pandemic continues. Patients' opinions on teledermatology have already been analyzed, but a current analysis during the COVID-19 pandemic is lacking. The purpose of this survey was to investigate the satisfaction of patients who had received dermatological advice via telephone during the COVID-19 pandemic and to analyze their general opinion about eHealth as well as possible limitations for a broad implementation. Ninety-one patients managed in the dermatology department using telephone consultation during the COVID-19 pandemic were interviewed. An anonymous questionnaire, including the established quality of life questionnaire (Dermatology Life Quality Index [DLQI]), was used. It was found that men were more satisfied with telephone consultations than women (p = 0.029), educational level and age did not correlate with satisfaction (p = 0.186 and 388, respectively), and the longer the waiting time for a telephone consultation, the lower the satisfaction (p = 0.001). Grouped analysis of all participants showed that the majority (54.0% n = 38/71) were "very happy" with the telephone consultation. Higher disease burden (DLQI) was associated with lower satisfaction (p = 0.042). The main stated reasons for using telemedicine were shorter waiting times (51.6% n = 47/91) and no travel requirement (57.1% n = 47/91). Almost one-quarter (23.1% n = 21/89) of patients would use teledermatology in the future, 17.6% (n = 16/89) would not, and 57.1% (n = 51/89) would only use it in addition to a traditional consultation with personal contact. In conclusion, most patients in the study group still preferred traditional face-to-face medical consultations to telephone consultations, but also desired an add-on telemedical tool. Dermatological care using more modern telemedicine technologies than telephone conferencing is needed to better address patients' desires, especially in times of the COVID-19 pandemic., (© 2021 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Around 20% of all children worldwide suffer from atopic dermatitis. Therefore, eczematous skin lesions and elevated serum immunoglobulin E (IgE) levels are common findings. Inborn errors of immunity (IEI) may be missed in the context of atopic dermatitis, and management and prognosis of these conditions can be substantially different. Children suffering from IEIs such as hyper-IgE syndromes, Wiskott-Aldrich syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, Omenn syndrome, the atypical complete DiGeorge syndrome, and skin barrier disorders like Comèl-Netherton syndrome and severe dermatitis-multiple allergies and metabolic wasting syndrome may present with additional red flags, which should raise a clinical suspicion for an underlying IEI. These red flags may include eczematous skin lesion manifesting prior to two months of life, disseminated or recurrent viral, bacterial, or fungal infections, mucocutaneous candidiasis, purpura, chronic diarrhea, or abnormalities in development or of connective tissue. A differential blood count, as well as a lymphocyte subset analysis, total immunoglobulin levels, and vaccination titers can help the clinician to decide whether a patient with eczematous skin lesions and elevated serum IgE should be referred to a clinical immunologist for a full immunological work-up and broad genetic analysis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)