Red scrotum syndrome: An update on clinicopathologic features, pathogenesis, diagnosis, and management.

The genital skin may be affected by a variety of dermatoses, be it inflammatory, infectious, malignant, idiopathic, or others. The red scrotum syndrome is characterized by persistent erythema of the scrotum associated with a burning sensation, hyperalgesia, and itching. Its cause is unknown, but proposed mechanisms include rebound vasodilation after prolonged topical corticosteroid use and localized erythromelalgia. The condition is chronic, and treatment is often difficult. Here we review the etiology, the physical and histopathologic findings, and the management of this condition. We also describe related conditions such as red scalp syndrome, red ear syndrome, and red vulva syndrome. Finally, we summarize the different cases reported in the literature and discuss the features that help in the differentiation of red scrotum syndrome from its mimickers.

Diagnostic Value of Plasmacytoid Dendritic Cells in Differentiating Pityriasis Lichenoides et Varioliformis Acuta From Lymphomatoid Papulosis.

ABSTRACT: Pityriasis lichenoides et varioliformis acuta (PLEVA) and lymphomatoid papulosis (LyP) can often demonstrate clinical and histopathologic overlap. A recent study demonstrated significant plasmacytoid dendritic cell (pDC) recruitment in lesions of PLEVA, whereas another study reported minimal pDC recruitment in lesions of LyP. To confirm the possible diagnostic value of pDCs in differentiating PLEVA and LyP, we compared the presence and distribution of pDCs and myxovirus protein A (MxA) expression (an indirect assessment of pDC activity). In total, 19 cases of PLEVA (16 patients) and 14 cases of LyP (11 patients) were examined using immunohistochemical stains for anti-blood-derived dendritic cell antigen-2 and MxA. Individual semiquantitative scoring systems were used to assess the immunohistochemical results, and a Mann-Whitney test with a subsequent 2-tailed P test was performed for statistical analysis. No statistically significant difference in the number of pDCs in both groups was found. However, most PLEVA cases (84%) demonstrated intense and diffuse MxA expression, whereas LyP cases (71%) demonstrated weak patchy staining (P < 0.007). Our study suggests that although additional studies may be needed to determine whether pDCs are more relevant to the pathogenesis of PLEVA or LyP, pDC activity through MxA staining may play a role in differentiating PLEVA from LyP and may serve as a platform for additional studies.

Genodermatoses with behavioural sequelae.

Children with genodermatoses are at an increased risk of developing behavioural disorders which may impart lasting damage on the individual and their family members. As such, early recognition of childhood mental health disorders via meticulous history taking, thorough physical examination, and disorder-specific testing is of paramount importance for timely and effective intervention. If carried out properly, prompt psychiatric screening and intervention can effectively mitigate, prevent or even reverse, the psychiatric sequela in question. To that end, this review aims to inform the concerned physician of the manifestations and treatment strategies relevant to the psychological sequelae of genodermatoses.

Characterizing the presence of neutrophil extracellular traps in neutrophilic dermatoses.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.

Genodermatoses with hearing impairment.

Hearing loss is a prominent feature in multiple genodermatoses. Underappreciation of auditory deficits can misdirect proper diagnosis by the treating dermatologist. This review reviews the anatomic, developmental, and embryologic aspects that characterize the ear and summarizes genodermatoses that have aberrant auditory findings. The latter are classified into neural crest, metabolic, pigmentary, craniofacial, and a miscellaneous category of disorders lacking specific cutaneous findings. The algorithms provided in this review enable treating dermatologists to better recognize and manage genodermatoses with ear involvement.

Imatinib-induced eruptive nevi.

Imatinib mesylate is a tyrosine kinase inhibitor used in the treatment of a variety of oncological conditions. It has been associated with a spectrum of pigmentary cutaneous side effects. Despite the well-known association of eruptive melanocytic nevi with the use of other tyrosine kinase inhibitors, this phenomenon has not been linked to the administration of imatinib. We present the first case of imatinib-induced eruptive nevi in an 18-year-old patient with acute lymphocytic leukaemia in remission.

Comparative characterization of sun exposed and sun protected skin-derived mesenchymal-like stem cells in variegate porphyria and healthy individuals.

BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual. METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients. RESULTS: Results showed that the percentage of CD105+ cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient. CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.

Osteoclast-Like Giant Cells: Focus on Entities Relevant to Dermatopathology and Underlying Pathogenesis.

ABSTRACT: Osteoclast-like giant cells (OLGCs) resemble osteoclasts with their abundant cytoplasm and well-developed organelles. OLGCs are characteristic features of giant cell tumor of the tendon sheath and giant cell tumor of soft tissue but they have also been described in numerous other cutaneous conditions. The diagnostic and prognostic significance of the presence of OLGCs is unknown. Here, we summarize the clinical entities that can exhibit these cells to avoid a histological overlap, affecting diagnosis and management.

Consanguinity rates among Syrian refugees in Lebanon: a study on genetic awareness.

Consanguineous marriage is a deeply rooted tradition in the Arab world. Such marriages are linked to higher rates of recessive genetic diseases. During the Syrian conflict, which started in 2011, around one million Syrian individuals became refugees in Lebanon. This study assessed the consanguinity rates among Syrian refugees living in Lebanon up to three successive consanguineous generations, and examined refugees' awareness of the possible consequences of consanguineous marriage and their attitudes towards consanguinity. Their knowledge of, and access to, premarital screening was also assessed. The study was conducted between January and May 2018. Several study sites representing refugees' distribution within the country were chosen. The study sample included 1008 interviewees from different families. Of those interviewed, 51.9% were in a consanguineous marriage. Interestingly, 23.9% were the product of consanguineous marriages themselves, and 17.9% were consanguineous for three successive generations. The interviewees generally knew about premarital screening, but the majority (61.9%) had not had the screening. The high rates of consanguinity in these Syrian refugees call for immediate action, including raising genetic awareness and providing appropriate genetic counselling. Despite the respondents' familiarity with premarital screening, there was a low rate of uptake of the test, underscoring the importance of providing better education to these refugees.

A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans.

Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment.

Tissue-resident memory T cells in the skin.

PURPOSE: Tissue-resident memory T (TRM) cells are a newly described subset of memory T cells. The best characterized TRM cells are CD8+ and express CD103 and CD69. These cells are non-recirculating and persist long term in tissues, providing immediate protection against invading pathogens. However, their inappropriate activation might contribute to the pathogenesis of autoimmune and inflammatory disorders. In the skin, these cells have been described in psoriasis, vitiligo, and melanoma among other diseases. METHODS: Literature review was done to highlight what is currently known on the phenotype and function of TRM cells and summarizes the available data describing their role in various cutaneous conditions. RESULTS: Resolved psoriatic skin and disease-naïve non-lesional skin contain a population of IL-17-producing TRM cells with shared receptor sequences that recognize common antigens and likely contribute to disease recurrence after cessation of therapy. In vitiligo, TRM cells produce perforin, granzyme B, and interferon-γ following stimulation by interleukin-15 and collaborate with recirculating memory T cells to maintain disease. In melanoma, increased accumulation of TRM cells was recently shown to correlate with improved survival in patients undergoing therapy with immune checkpoint inhibitors.

Neutrophil Extracellular Traps are Present in Immune-complex-mediated Cutaneous Small Vessel Vasculitis and Correlate with the Production of Reactive Oxygen Species and the Severity of Vessel Damage.

Formation of neutrophil extracellular traps has been implicated in autoimmunity. However, the presence and clinical relevance of neutrophil extracellular traps in immune-complex-mediated cutaneous small and medium vessel vasculitides has not been investigated. This study retrospectively analysed 72 patients with histology-proven hypersensitivity vasculitis (n = 21), IgA vasculitis (n = 22), urticarial vasculitis (n = 22), erythema elevatum diutinum (n = 3) and polyarteritis nodosa (n = 4). Neutrophil extracellular traps were detected in hypersensitivity vasculitis, IgA vasculitis, urticarial vasculitis and erythema elevatum diutinum, but not in polyarteritis nodosa lesions. Neutrophil extracellular traps were found around inflamed vessels, and their formation was highest early after the onset of vasculitis and decreased progressively thereafter. Neutrophil extracellular traps were strongly correlated with the histological severity of vasculitis and the production of reactive oxygen species. Both hypersensitivity vasculitis and IgA vasculitis showed significantly more neutrophil extracellular traps than did urticarial vasculitis, independent of the histological severity and duration of vasculitis. These results provide evidence on the implication of neutrophil extracellular traps in the early phases of immune-complex-mediated small vessel vasculitis.

SuPAR, a potential inflammatory mediator in psoriasis pathogenesis.

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild-moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.

Genodermatoses with teeth abnormalities.

Many genodermatoses exhibit abnormal teeth findings. Studies examining these entities are scarce and narrow in their scope. This paper reviews the evolution, development, and structure of the tooth and provides a summary of genodermatoses with aberrant dental findings. The latter are classified according to the abnormal dental findings: periodontal disease, anodontia/oligodontia/hypodontia, polydontia, enamel hypoplasia, natal teeth, dental pits, and others. Finally, we provide an algorithm that dermatologists and dentists can follow to better recognize genodermatoses with dental involvement.

Neuroendocrine Differentiation of Skin Tumors: A Comprehensive Review.

Neuroendocrine differentiation is characterized by endocrine and neuronal features with prominent dense secretory granules and neuropeptides. Neuroendocrine differentiation of skin tumors is of unknown clinical significance. Nonetheless, the acknowledgment of this line of differentiation is important to prevent diagnostic pitfalls and subsequent inappropriate management. This review aims at summarizing the skin neoplasms that can express neuroendocrine markers.

Investigating the presence of neutrophil extracellular traps in cutaneous lesions of different subtypes of lupus erythematosus.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, little is known about the implication of NETs in cutaneous lupus. In this case series of 30 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different subtypes of lupus (5 with discoid lupus or DLE, 5 with subacute cutaneous lupus or SCLE, 11 with acute cutaneous SLE, 7 with lupus panniculitis and 2 with chilblains). Immunofluorescence was performed on formalin-fixed paraffin-embedded skin biopsies using antibodies against neutrophilic granules (elastase, myeloperoxidase, PR-3 proteins and citrullinated histone 3). Dihydroethidium staining was performed to detect reactive oxygen species (ROS), known inducers of NETs. NETs were detected in the different subtypes of cutaneous lupus as well as in cutaneous lesions of SLE. The amounts of neutrophils producing NETs were significantly higher in lupus panniculitis (49%), acute cutaneous SLE (41%) and DLE (32%), in comparison with SCLE (5%) and chilblains (0%). This suggests that NETs might be associated with more tissue damage and scarring. ROS were observed in the different cutaneous subtypes of lupus independent of NETs.

Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient's skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

CHILD syndrome: A modified pathogenesis-targeted therapeutic approach.

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.

Orf virus infection.

Orf virus (ORFV) is an important pathogen responsible for a highly contagious zoonotic viral infection that threatens those who handle sheep and goats. Orf virus is the prototype of the Parapoxvirus genus, and its resilience in the environment and ability to reinfect its host has contributed to the spread and maintenance of the infection in many species. In healthy humans, the disease usually resolves spontaneously within 3 to 6 weeks. There is no specific treatment and many different approaches such as use of imiquimod, cidofovir, curettage, shave excision, cryotherapy, and electrocautery have all been reported to be successful, without supporting evidence from controlled clinical trials. Throughout its interaction with the different hosts, ORFV has evolved a strategy for immune evasion via the development of an array of virulence factors. The interaction of ORFV with the immune system has been the subject of research for decades. Whole inactivated ORFV has been used as a type of immunomodulating drug; a so called paramunity inducer proposed as both a preventative and a therapeutic immunomodulator across various species. Additional research on the remarkable strategies underlying ORFV infection could lead to improved understanding of skin immunity.