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Background Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified. Objectives We aimed to identify the genetic cause of HLP. Methods For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA ­extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed ­paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated. Results In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46–62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients. Conclusions Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.

Supplementary Figures S1-S4 from Constitutive Suppressor of Cytokine Signaling 3 Expression Confers a Growth Advantage to a Human Melanoma Cell Line

The growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, whereas late stage melanoma cells have often been reported to be “multi-cytokine–resistant.” Here, we analyzed the melanoma cell line 1286, resistant towards the growth-inhibitory effects of interleukin 6 (IL-6), and oncostatin M (OSM), to better understand the mechanisms underlying cytokine resistance. Although the relevant receptors gp130 and OSMR are expressed at the cell surface of these cells, cytokine stimulation hardly led to the activation of Janus kinase 1 and signal transducer and activator of transcription (STAT)3 and STAT1. We found a high-level constitutive expression of suppressors of cytokine signaling 3 (SOCS3) that did not further increase after cytokine treatment. Importantly, upon suppression of SOCS3 by short interfering RNA, cells became susceptible towards OSM and IL-6: they showed an enhanced STAT3 phosphorylation and a dramatically increased STAT1 phosphorylation. Moreover, suppression of SOCS3 rendered 1286 cells sensitive to the antiproliferative action of IL-6 and OSM, but not of IFN-α. Interestingly, SOCS3–short interfering RNA treatment also increased the growth-inhibitory effect in cytokine-sensitive WM239 cells expressing SOCS3 in an inducible way. Thus, SOCS3 expression confers a growth advantage to these cell lines. Constitutive SOCS3 mRNA expression, although at lower levels than in 1286 cells, was found in nine additional human melanoma cell lines and in normal human melanocytes, although at the protein level, SOCS3 expression was marginal at best. However, in situ analysis of human melanoma specimens revealed SOCS3 immunoreactivity in 3 out of 10 samples, suggesting that in vivo SOCS3 may possibly play a role in IL-6 resistance in at least a fraction of tumors. (Mol Cancer Res 2007;5(2):271–81)

Lyme borreliosis (LB) is the most common tick-borne infection in Europe and North America. Polymerase chain reaction (PCR) is an important tool to confirm the diagnosis, but not always successful, especially when organisms are sparse. We developed a novel, seminested real-time PCR assay [target: 5S-23S intergenic spacer region (IGS)] and compared it with 3 well-established conventional PCR assays (IGS/OspA/real-time IGS) on 596 formalin-fixed, paraffin-embedded routine skin biopsies. The seminested real-time assay identified 46 cases of borreliosis while 25, 27, and 38 were identified by the 3 other assays, respectively (P 0.01, P 0.02, and P 0.42; significance P0.05). Clinicopathologic and immunophenotypic analysis of PCR-positive cases revealed 38 erythema migrans (EM), 6 Borrelia lymphocytomas, and 2 acrodermatitis chronica atrophicans (ACA). In the 44 PCR-confirmed cases, plasma cells were present in only a third of EM cases. By contrast, CD123-positive plasmacytoid dendritic cells were common (74%) and therefore are unlikely to be helpful in the differential diagnosis between EM and tumid lupus erythematosus. A loss of CD34 in a third of all LB specimens limits its diagnostic value in the differential diagnosis with morphea. Interstitial macrophages were common in cutaneous LB (42/43) forming interstitial granulomas in a third of all cases, and 3/38 EM, 3/6 Borrelia lymphocytomas, and 1/2 ACA were only identified by the new seminested real-time assay, suggesting that it is especially helpful in confirming the diagnosis of Borrelia lymphocytoma.

This article reviews non-infectious inflammatory dermatoses with mainly neutrophilic infiltrates and the formation of pustules. The infiltrate containing neutrophils may either be mild as in urticaria or very dense, even with leukocytoclasia as in Sweet syndrome or pyoderma gangrenosum. The location, interaction with epithelial structures and density of the neutrophilic infiltrate may be useful to distinguish these dermatoses. Neutrophilic infiltrates and pustular eruptions are caused by different non-infectious immunomechanisms. Neutrophilic dermatoses are of high interest, as they may present dermatological reaction patterns of underlying benign or malignant conditions.

Coronavirus disease 2019 (COVID-19) is a systemic disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that frequently presents with skin manifestations. The five most common skin lesions are pseudo-chilblain and maculopapular, urticarial, vesicular, and livedo/necrotizing skin lesions. These skin lesions are of diagnostic and prognostic relevance. For example, in children, typical skin lesions may indicate a life-threatening inflammatory syndrome, which rarely occurs after corona infection. Skin lesions have also been described after COVID-19 vaccination. These usually show an uncomplicated, self-limiting course and therefore do not represent a contraindication for completing the vaccination status in the vast majority of cases.COVID-19 (Coronavirus Disease 2019) ist eine durch SARS-CoV‑2 (schweres akutes respiratorisches Syndrom Coronavirus-2) verursachte Systemerkrankung, die häufig mit Hautmanifestationen einhergeht. Die 5 häufigsten Hautläsionen sind der Pseudo-Chilblain sowie makulopapulöse, urtikarielle, vesikuläre und livedoartige/nekrotisierende Hautveränderungen. Diese Hautläsionen haben eine diagnostische und prognostische Relevanz. So können beispielsweise bei Kindern typische Hautläsionen auf ein lebensbedrohliches inflammatorisches Syndrom hinweisen, das selten nach einer Corona-Infektion auftritt. Auch nach COVID-19-Impfungen wurden Hautveränderungen beschrieben. Diese zeigen meist einen komplikationslosen, selbstlimitierenden Verlauf und stellen daher in den allermeisten Fällen keine Kontraindikation zur Komplettierung des Impfstatus dar.

Introduction Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a clinically very well-defined drug eruption, but the histopathological findings are still considered to be nonspecific. Objectives To characterize the histopathological and immunophenotypical features of SDRIFE. Material and methods We performed a retrospective study that identified 11 biopsies from 9 patients with SDRIFE. The histopathological features were analyzed in conjunction with the immunohistochemical findings. Results The most common histopathological feature was basal cell vacuolization, which was often associated with necrotic keratinocytes and focal spongiosis. TIA1+ T cells and neutrophils were frequently detected in the epidermis and at the dermoepidermal junction. The dermal inflammatory infiltrate was mixed, consisting of CD3+ T cells, macrophages, granulocytes, low numbers of CD20+ B cells, and plasma cells. A combination of histopathological patterns was observed in 5 cases. The most frequent combined histopathological patterns were interface dermatitis, spongiotic dermatitis, and psoriasiform dermatitis. Other histopathological patterns found in different combinations were pustular dermatitis, perivascular and interstitial neutrophilic dermatitis, and interstitial granulomatous dermatitis. In the other 4 cases, a single histopathological pattern predominated, such as psoriasiform dermatitis, vacuolar interface dermatitis of erythema multiforme-like type, or superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils. Conclusions SDRIFE is characterized histologically by a vacuolar interface dermatitis induced by cytotoxic T lymphocytes and neutrophilic granulocytes. This pattern may be obscured by accompanying spongiotic, psoriasiform, or pustular features combined with a mixed superficial and sometimes deep dermal infiltrate.

Ichthyosen sind hereditare Verhornungsstorungen, die isoliert/nichtsyndromal oder mit assoziierten Erkrankungen an inneren Organen (syndromal) auftreten und bei Neugeborenen zu lebensbedrohlichen Komplikationen fuhren konnen. Die Identifizierung der genetischen Ursachen hat zum Verstandnis der molekularen Mechanismen, aber auch zur Reklassifizierung gefuhrt. Auch die pathologischen Veranderungen der Hautbiopsien wurden genauer charakterisiert. Dabei konnten bestimmte histologische Muster definiert werden, die sich an den Differenzierungsstorungen der Epidermis, aber auch dem dermalen Entzundungsmuster orientieren. Erganzende histo- und immunhistochemischen Methoden erlauben teils eine prazise Diagnose, zumindest aber eine Eingrenzung der Differenzialdiagnosen.

Zusammenfassung Hintergrund Das Netherton-Syndrom (NS) ist eine seltene, schwer verlaufende, autosomal rezessive Form einer kongenitalen Ichthyose, verbunden mit einem charakteristischen Defekt des Haarschaftes (Trichorrhexis invaginata), Erythrodermie und einer ausgeprägten Atopieneigung auf dem Boden eines veränderten Immunsystems mit erhöhten IgE-Werten. Seine Inzidenz wird mit 1:100 000 bis 1:200 000 angegeben. Die Ursache sind Mutationen im Gen SPINK5 (5q31-q32), das für den Serinprotease-Inhibitor LEKTI kodiert. Betroffene Neugeborene zeigen ein nicht einheitliches Bild einer generalisierten Erythrodermie mit Schuppung der Haut bis zum Vollbild eines Kollodiumbabys. Eine schwerwiegende Komplikation im Neugeborenenalter ist die hypernatriämische Dehydratation auf dem Boden der unzureichenden Barrierefunktion der Haut. Im Verlauf stehen rezidivierende Infekte, Atopieneigung, Diarrhoen und intestinale Malabsorption (Enteropathie) mit einer damit verbundenen Gedeihstörung im Vordergrund. Patient/Methode Wir berichten über ein Neugeborenes mit NS, welches post partum neben einer ausgeprägten Erythrodermie durch eine schwer zu therapierende hypernatriämische Dehydratation auffiel. Ergebnis Die Untersuchung einer Hautprobe unserer Patientin zeigte eine für das NS typische und richtungsweisende psoariasiforme Dermatitis mit Fehlen des LEKTI-Proteins. Die schweren rezidivierenden und behandlungsbedürftigen Elektrolytentgleisungen standen in der Neonatalperiode als lebensbedrohliche Komplikation im Vordergrund. Schlussfolgerung Bei Neugeborenen mit Erythrodermie muss an das seltene Krankheitsbild eines NS gedacht werden, da die betroffenen Kinder durch Elektrolytentgleisungen sehr gefährdet sind und diese mit einer hohen Letalität einhergehen. Diagnose und Therapie des NS erfordern eine sehr gute interdisziplinäre Zusammenarbeit zwischen Neonatologen, Intensivmedizinern, Dermatologen sowie im Verlauf Infektiologen und Allergologen. Eine engmaschige Weiterbetreuung bis in das Jugendalter ist unabdingbar.

One of the most common patterns of presentations that have been described in COVID-19 patients includes the erythematous/papular/morbilliform eruptions. However, actually, the diffuse exanthems containing macules and papules were not specific to COVID-19, and even histopathology does not show any specific signs that could help to differentiate COVID-19 skin lesions from non-COVID-19 causes such as drugs or other viral infections. We present the case of a COVID-19-positive woman with a morbilliform rash, whose skin biopsy showed the presence of some peculiar cytopathic epidermal changes that could represent a possible distinctive histopathological feature related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection The presence of viral particles in the keratinocytes with additional positivity of endothelial cells and eccrine glands by immunohistochemistry using an anti-SARS-CoV-2 Spike S1 antibodies supports a causal relation of the lesions with SARS-CoV-2 infection.

Background Rheumatoid arthritis is one of the most common autoimmune disorders. In addition to chronic arthritis, rheumatoid arthritis may present a variety of extra-articular manifestations, most commonly of the skin. Objectives Cutaneous manifestations associated with rheumatoid arthritis can be diverse, both specific and nonspecific. Which dermatoses should lead you to the diagnosis of an underlying rheumatoid arthritis? Methods Evaluation of exemplary overviews, case presentations and relevant textbook articles. Results Rheumatoid arthritis presents various specific and nonspecific skin manifestations. Besides visual diagnosis like classic rheumatoid nodules a histopathologic correlation or an interdisciplinary approach is often needed, such as for diagnosis of pyoderma gangrenosum. Conclusions The early detection and correct classification of cutaneous manifestations associated with rheumatoid arthritis can be groundbreaking for a successful therapy and a consequently better prognosis for patients with rheumatoid arthritis. Therefore dermatologists bear responsibility in the patient-centered care.

Onychomycosis is common. Diagnosis can be confirmed by various methods; a commonly used method is the histological examination of nail clippings. A deep learning system was developed and its diagnostic accuracy compared with that of human experts. A dataset with annotations for fungal elements was used to train an artificial intelligence (AI) model. In a second dataset (n=199) the diagnostic accuracy of the AI was compared with that of dermatopathologists. The results show a non-inferiority of the deep learning system to that of analogue diagnosis (non-inferiority margin 5%) with respect to specificity and the area under the receiver operating characteristic curve (AUC). The AI achieved an AUC of 0.981. One limitation of this system is the need for a large number of training images. The AI had difficulty recognizing spores and confused serum or aggregated bacteria with fungal elements. Use of this deep learning system in dermatopathology routine might help to diagnose onychomycosis more efficiently.

ZusammenfassungEin 26-jähriger Sportler stellte sich in unserer phlebologischen Ambulanz zur Diagnostik und Therapie bei sichtbarer Varikosis am linken Bein vor. Sonografisch stellte sich eine insuffiziente Vena saphena magna links dar. Es wurde eine VNUS-Closure der VSM links komplikationslos durchgeführt. Trotz sonografisch unauffälligen Kontrollen berichtet der Patient im weiteren Verlauf über ein zunehmendes Schweregefühl und eine Verhärtung der Haut. In der Histologie konnte eine eosinophile Fasziitis nachgewiesen werden. Bisher gibt es keine Berichte zum Zusammenhang von chronisch-venöser Insuffizienz, der endoluminalen Behandlung und eosionphiler Fasziitis. Der Fallbericht stellt eine seltene, aber in diesem Fall wichtige Differenzialdiagnose bei postinterventionellen venösen Beschwerden dar.

Hand-foot-mouth disease (HFMD) is a common contagious viral infection usually affecting infants and children. Recently, literature on HFMD in adults is increasing. It has been reported that adults often present with unusual exanthems with similarities to erythema multiforme (EM). No study has so far compared the histologic features of HFMD with those of EM.Histopathologic features in 7 biopsies of 6 adult patients with HFMD are compared with biopsies from 9 patients with EM to identify the best criteria for differentiation.HFMD and EM both have a perivascular lymphocytic infiltrate together with epidermal necrosis, spongiosis, ballooning, and reticular alteration. However, large numbers of neutrophils in parakeratosis (P0.05), in the viable epidermis (P001), or neutrophils forming intraepidermal collections (P0.05) are significantly more common in HFMD. In HFMD, necrotic keratinocytes are emphasized in the upper third of the epidermis (P0.05), whereas the lower third is typically involved more in EM. Neutrophils are significantly more common and more numerous in the dermal infiltrate of HFMD compared with EM (P0.01) Extravasated erythrocytes in the epidermis are more common and more numerous in HFMD (P0.05).Lesions of EM and HFMD can be differentiated based on the amount of neutrophils in the epidermis and in the dermal infiltrate, which are significantly more numerous in HFMD. In addition, necrosis is emphasized in the upper part of the epidermis in HFMD and in the lower part of it in EM.

Although it is unquestionable that monoclonal gammopathy causes occlusive nonvasculitic vasculopathy,1 it is not clear yet, if it can cause immunoglobulin-mediated leukocytoclastic vasculitis (LcV) and how vigorously both conditions should be treated in monoclonal gammopathy of unclear significance (MGUS). In the recent nomenclature of cutaneous vasculitides (addendum to the CHCC2012),2 vasculitis in MGUS is mentioned as a possible, so-far unproven entity. Previous case reports did not sufficiently or explicitly distinguish it from occlusive vasculopathy. Adding to this dilemma is a lack of consensus with oncologists if or when chemotherapies are justified in MGUS with a paraprotein-associated disease. We provide evidence by means of 2 cases of MGUS that monoclonal gammopathy can cause primary immunoglobulin-mediated LcV and that its oncologic treatment abolishes it.

The nomenclature system agreed upon by the Chapel Hill Consensus Conference (CHCC) with respect to the terminology and precise definition of the various types of vasculitis has gained widespread interdisciplinary and international acceptance. As the revised version from 2012 (CHCC 2012) does not address the special features of vasculitis of the skin, it has recently been supplemented with an addendum containing the nomenclature of cutaneous vasculitides (D-CHCC). The present article provides the German translation of the terms and defintions of the D-CHCC as well as additional explanatory comments. The goal is to enable German-speaking health care providers to more readily apply these defined terms - which are based on interdisciplinary consensus - in everyday clinical practice and to facilitate assessment of their practicability and relevance in patient care. If the majority of cutaneous vasculitides diagnosed can be matched with any of the defined entities presented herein, it might subsequently be possible to develop a classification system and diagnostic algorithms.

Ichthyoses are inborn keratinization disorders affecting the skin only (non-syndromic) or are associated with diseases of internal organs (syndromic). In newborns, they can be life-threatening. The identification of the gene defects resulted in reclassification and a better understanding of the pathophysiology. Histopathologic patterns include orthohyperkeratosis with a reduced or well-developed stratum granulosum, hyperkeratosis with ortho- and parakeratosis with preserved or prominent stratum granulosum, and epidermolytic ichthyosis. Another pattern features “perinuclear vacuoles and binucleated keratinocytes”, which is associated with keratin mutations. Some ichthyoses are histologically defined by psoriasis-like features, and distinct subtypes show follicular hyperkeratosis. In addition to histological and immunohistochemical methods, these patterns allow a better histopathologic diagnosis.

Ichthyoses are hereditary cornification disorders that occur in isolation (nonsyndromic) or with associated internal diseases (syndromic) and can lead to life-threatening complications. The identification of the genetic causes has led to an understanding of the molecular mechanisms, but also to reclassification. The pathological changes in skin biopsies were also more precisely characterized. Certain histological patterns could be defined, which are based on the defects of epidermal differentiation but also on the inflammatory pattern. Complementary histo- and immunohistochemical methods sometimes allow a precise diagnosis, or at least a limitation of the differential diagnoses.

This article reviews noninfectious inflammatory dermatoses with mainly neutrophilic infiltrates and the formation of pustules. The infiltrate containing neutrophils may either be mild as in urticaria or very dense, even with leukocytoclasia, as in Sweet syndrome or pyoderma gangrenosum. Neutrophilic infiltrates and pustular eruptions are caused by different noninfectious immunomechanisms. For some of them, mutations have been found (e.g. NLRC4 mutation in cryopyrin-associated periodic syndromes (CAPS) leading to activation of the inflammasome; IL36RN mutation in pustular psoriasis resulting in uncontrolled IL36 signaling). Neutrophilic dermatoses are of high interest, as they may be the cause of underlying benign or malignant conditions. In recent years, efficient targeted therapies have been developed.

We describe a 33‐year‐old male patient who developed hypopigmentation around his melanocytic nevi with disappearance of the nevi in August 2018. In June 2016 he had been diagnosed with highly active RRMS and treated with alemtuzumab in September 2016 for the first time. In September 2017 another cycle of alemtuzumab was administered. The patient’s family history for vitiligo was unremarkable and he had no autoimmune thyroid disease.

is missing (Short communication)

Imatinib mesylate (Glivec; Novartis AG, Basel, Switzerland) is a tyrosine kinase inhibitor which is used in the treatment of oncologic diseases like chronic myeloid leukemia and gastrointestinal stroma tumor (GIST). Among cutaneous side effects, bullous reactions are rare. The authors describe the case of a 66-year-old woman developing blistering and skin fragility on her hands, foot, lower legs, and back after intake of imatinib for treatment of GIST. Biopsy showed vacuolar alteration at the dermoepidermal junction (DEJ) associated with a few lymphocytes and a subepidermal blister. The upper papillary dermis below the vacuolar alteration and below the blister showed hyalinization and loss of elastic microfibrils. Direct immunofluorescence was negative for deposits of immunoglobulins. Immunofluorescence on cryosections revealed loss of laminin and collagen IV in vacuoles at the DEJ. Electron microscopy showed dissolution of lamina lucida and lamina densa of the basement membrane below as well as next to the vacuoles and blister. In conclusion, the authors present the first patient with GIST with blistering and skin fragility due to imatinib therapy. As a pathophysiological explanation the authors propose loss of laminin and collagen IV at the DEJ leading to basement membrane instability and blistering. This case also suggests additional features reminiscent of lichen sclerosus induced by imatinib, a drug which is actually known for its antifibrotic effects.