Disorders Of Keratinization Research Articles

Conceptual Contextualization of Neutrophilic Dermatoses

Abstract: Neutrophilic dermatoses are defined as inflammatory skin diseases characterized by sterile infiltration of polymorphonuclear neutrophils into various cutaneous layers. Although, in many cases, neutrophilic dermatoses represent the cutaneous counterpart of autoinflammatory diseases, this is not always the case, and there are other causes associated with this group of diseases, such as the administration of certain drugs or an underlying tumor. However, understanding the autoinflammatory context in which most of these entities develop, as well as their close relationship with autoimmunity, is key to comprehending their pathogenesis. In addition, understanding the mechanisms by which neutrophils migrate to the dermis and become activated is fundamental for interpreting the morphological findings of these biopsies. Finally, the description of a new group of neutrophilic dermatoses in recent years, in relation to keratinization disorders, has been crucial for understanding the best therapeutic approach for these difficult-to-manage entities.

Developing a core outcome set for Netherton syndrome: An international multi-stakeholder e-Delphi consensus study.

Netherton syndrome (NS; OMIM#256500) is a rare and severe disorder of epidermal maturation and keratinization caused by pathogenic variants in the serine protease inhibitor Kazal type 5 (SPINK5), leading to severe skin barrier impairment. Although effective treatment is crucial for NS patients, there is a lack of knowledge on what the best treatment options are for these patients. Large heterogeneity in reported outcomes and measurement instruments hinders accurate comparison of treatment results across studies and the development of a treatment guideline. Therefore, we aimed to develop a core outcome set (COS) for NS that can be used in clinical care and research. This study was performed in accordance with the recommendations of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. After identification of outcomes through a literature search and classification based on the International Classification of Functioning and taxonomies published by the COMET initiative, discussion groups were organized at the 2nd International Netherton Congress 2022 to finalize the provisional outcome list. Through a 2-round e-Delphi, 41 stakeholders (patients and family members, professionals, and representatives of industry) from 14 countries rated the importance of the outcomes using a 9-point Likert scale. An online consensus meeting attended by 14 stakeholders finalized the COS. The core outcome set for NS comprised 21 outcomes in 10 domains. These included four 'skin' outcomes, two 'sensation' outcomes, two 'side-effects of treatment' outcomes, one 'vitality' outcome, one 'emotional functioning' outcome, two 'physical development' outcomes, two 'nutrition' outcomes, two 'infections' outcomes, two 'allergies' outcomes, and three 'assessment results' outcomes. In this study, consensus was reached on 21 outcomes to be included in the COS for NS. The selection of outcomes in the COS underlines that NS not only affects the skin, but is a disease requiring a broad multidisciplinary approach in clinical care and research. International implementation of this COS will lead to more uniform reporting, thereby enabling comparison of study results, which may facilitate future treatment guideline development. The next step is to further conceptually define the outcomes and reach consensus on how the measure these.

Disseminated Superficial Actinic Porokeratosis: A Systematic Treatment Review.

Disseminated superficial actinic porokeratosis (DSAP) is a disorder of keratinization characterised by small, brown plaques with elevated keratotic rims, typically occurring on sun exposed areas. DSAP poses a risk for malignant transformation, emphasising the need for effective management strategies. The aim of this study was to review the current reported management options for DSAP. This systematic review was based on a comprehensive search of databases (Cochrane, PubMed, Medline, Embase, Emcare, ProQuest, Web of Science, CINAHL) from inception to 15 March 2024. Studies reporting management of DSAP were included irrespective of study design. Of 923 citations, 61 studies were included, predominantly comprising case reports and retrospective case series. A limited number of randomized and open-label trials were identified. Various treatment modalities were reported, including topical and systemic agents, photodynamic therapy, and laser therapy. Multiple management options are available for DSAP, including topical and systemic agents, photodynamic therapy and laser treatments. However, these approaches vary in their balance between efficacy and toxicity. Currently, there is a paucity of high-quality clinical trial data to guide treatment decisions. Further studies are required to determine the most effective and safe management strategies for DSAP. PROSPEROREGISTRATION: CRD42024514558.

Satisfactory Clinical Response to Erlotinib in a Patient Diagnosed with Olmsted Syndrome.

Olmsted syndrome is a rare congenital keratinization disorder characterized by mutilating palmoplantar keratoderma (PPK), often accompanied by flexion deformity, periorificial keratotic plaques, and hair abnormalities. The majority of Olmsted syndrome cases are attributed to mutations in the TRPV3 (Transient receptor potential vanillin 3) gene(1). Herein, we aim to present a sporadic case of Olmsted syndrome with a recurrent c1717G>T p.Gly573Cys variant in the TRPV3 gene, demonstrating clinical improvement with the epidermal growth factor inhibitor Erlotinib.

A case of revertant mosaic-like normal-looking spots in a patient with erythroderma with IL36RN and CARD14 heterozygous mutations.

An 89-year-old Japanese woman presented with erythroderma associated with significant scaling. A histological examination showed acanthosis with hyperkeratosis and hyperkeratinization of the hair follicles. Genetic analyses using DNA from the peripheral blood revealed heterozygous mutations in IL36RN (c.115+6T>C) and CARD14 c.2648G>A (p.Arg883His). Based on these findings, we diagnosed her with erythroderma attributable to autoinflammatory keratinization disease. She then developed more than 30 small, round, well-defined, spots on her back and extremities that appeared histologically normal. We suspected that these spots might be revertant mosaicism. Immunohistochemical staining with p65, which is a component of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), revealed nuclear staining in epidermal keratinocytes in erythematous lesions, but not in the normal-looking spots. However, mutations in IL36RN and CARD14 unexpectedly persisted in the epidermis and dermis of the normal-looking spots.

Strategies for Differential Diagnosis and Management of Ichthyosis in Newborns

Congenital ichthyosis represents agroup of heterogeneous inherited skin diseases characterized by generalized keratinization disorder in the form of hyperkeratosis, caused by abnormalities in epidermal differentiation. The neonatal period is crucial for patients with ichthyosis due to the risk of developing complications, comorbidities, and fatal outcomes. Most complications arise from impaired skin barrier function. This article discusses the manifestations of ichthyosis in newborns, describes risks and complications, and suggests strategies for monitoring and treating patients. Purpose of the study: to present contemporary data on differential diagnosis and treatment strategies for newborn patients with congenital ichthyosis. Materials and Methods: review of Russian and international sources dedicated to the etiology, diagnosis, and treatment of ichthyosis was conducted. Results: Differential diagnosis of ichthyosis in the neonatal period is acrucial task, hence the most life-threatening subtypes are considered. The most severe progression with ahigh risk of fatal outcomes is characteristic of Harlequin ichthyosis. Collodion baby presents with less pronounced symptoms, is not afinal diagnosis, and may later develop clinical manifestations typical of ichthyosiform erythroderma, lamellar ichthyosis, or self-resolving congenital ichthyosis. Netherton syndrome is characterized by acombination of congenital ichthyosis with structural abnormalities of the hair shaft and apropensity for atopy. Epidermolytic ichthyosis, accompanied by the formation of blisters and erosions on the skin, requires differential diagnosis not only with other forms of ichthyosis but also with bullous epidermolysis, staphylococcal scalded skin syndrome, and toxic epidermal necrolysis. Every newborn with described manifestations requires support from amultidisciplinary team of specialists and timely therapeutic and diagnostic measures aimed at preventing the development of complications and deterioration of the patient’s condition. Conclusion: An analysis of global literature data and the practical experience of the authors indicate the complexities of differential diagnosis of ichthyosis forms in the neonatal period. To improve skin condition, prevent infectious complications, and correct electrolyte and respiratory disturbances, symptomatic treatment should begin before adefinitive diagnosis is established.

Establishment of a Mouse Model for Porokeratosis Due to Mevalonate Diphosphate Decarboxylase Deficiency.

Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase (MVD) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis. In this research, we constructed K14-CreERT2-Mvdfl/fl mice using the Cre-LoxP system to create a mouse model for in-depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA-seq, and Western Blot analysis were performed. Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL-17A and IL-1β, and a decreased Loricrin level in epidermal Mvd-deficient mice. Compared with the wild-type (WT) group, Mvd deficiency activated the expression of lipid metabolism-related proteins. We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches.

Dysregulation of Aquaporin-3 and Glyceryl Glucoside Restoring Action in Hidradenitis Suppurativa in Vitro Models.

Aquaporin-3 (AQP3) is an aquaglyceroporin and peroxiporin that plays a crucial role in skin barrier homeostasis. Dysregulated AQP3 expression has been observed in different inflammatory skin conditions. Hidradenitis Suppurativa (HS) is an autoinflammatory keratinization disease that typically appears between 10 and 21 years of age, characterized by alteration of skin barrier homeostasis. To evaluate in vitro the role of AQP3 in the development of HS, we performed real-time PCR and Western blot to analyze gene and protein levels in human keratinocyte cell lines knock-out (KO) for NCSTN and PSENEN genes, simulating genetic-associated HS. Additionally, we investigated the impact of Glyceryl Glucoside (GG) on biological processes by performing MTT, scratch, proliferation assays and proteome studies. We detected a significant decrease of the levels of AQP3 gene and protein in KO cell lines. GG effectively elevated the levels of mRNA and protein, significantly decreased the hyperproliferation rate, and enhanced cell migration in our in vitro model of genetic Hidradenitis Suppurativa. Pathway enrichment analysis further confirmed GG's role in the migration and proliferation pathways of keratinocytes. Our results suggest that AQP3 may act as a new novel actor in HS etio-pathogenesis, and GG could be further explored as potential treatment option for managingHSinpatients.

Vitamin D Supplementation in Congenital Ichthyosis: A Case Series.

Ichthyosis is a group of genetic keratinization disorders characterized by excessive scaling that is associated with hyperproliferative epidermis and/or cellular retention. Whereas normal outer epidermis thickness is 25 μm, it can be 10-fold greater in patients with ichthyosis. As a result, photoactivation of 7-dehydrocholesterol is impaired, causing systemic vitamin D deficiency.In this case series, 25 patients with congenital ichthyosis with vitamin D deficiency (<10 ng/mL) were supplemented with 60,000 IU of vitamin D3 for 10 days followed by daily allowance of 400 to 600 IU of vitamin D3 and 40 mg/kg per day of elemental calcium. The authors assessed improvement in cutaneous scaling and body and tested patients' blood and urine samples at day 1, day 10, 1 month, and 3 months. They also documented patients' Dermatology Life Quality Index score before and after treatment.All patients had normal vitamin D levels; supplementation was discontinued for two patients who reached a level of 100 ng/mL within 10 days. Subjective improvement of symptoms (dryness of the skin, allergic rhinitis, tightness of the skin, and scaling) was observed by both the provider and the patients. There was remarkable improvement in symptoms of severe ichthyosis such as lamellar ichthyosis (tightness of the skin and scaling). Marked improvement in Dermatology Life Quality Index score was also noted.This case series demonstrated remarkable symptomatic relief with vitamin D supplementation in patients with congenital ichthyosis; however, additional research should be conducted with larger sample sizes to support these findings.

Spectrum of Inpatient Pediatric Dermatology Cases at a Tertiary Health Care Centre in South India.

Background Dermatologists and pediatricians commonly encounter pediatric dermatology cases in their clinical practice, and the number has risen for the past decade. While numerous studies have addressed adult inpatient dermatology cases, there is a lack of data on the same for the pediatric population. Aim The study aimed to investigate the spectrum and outcomes of inpatient pediatric dermatology cases at a tertiary health care center. Methods This was a hospital-based, cross-sectional study that included children under the age of 16 years with primary skin disorders who were admitted to the pediatric dermatology unit. Patients were categorized into six groups based on their provisional diagnosis for better analysis. Results A total of 105 children were admitted, with a male-to-female ratio of 1.2:1. The average age of admitted children was 5.8 years, with the majority belonging to the school-going age group, accounting for 44% of the patients. Conclusion Inflammatory skin conditions like childhood psoriasis and erythroderma were the most common group of disorders presented to us, followed by hereditary conditions like keratinization disorders and mechanobullous disorders. Pediatric dermatology emergencies (PDEs) require an inter-professional approach for timely intervention and management.

Bony side-effects in acitretin treatment: is monitoring required?

Acitretin is an oral retinoid and the active metabolite of etidronate. While most commonly used for the treatment of inflammatory disorders, its indications extend to disorders of keratinization in the paediatric population. In the midst of a safety announcement on the side-effects of isotretinoin by the UK Commission on Human Medicines, a debate on whether acitretin monitoring should also be updated is encouraged.

Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1β as a key mediator, orchestrating an NF-κB-mediated IL-1β-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1β. With the central role of IL-1β underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1β antagonists in PRP.

Conventional and Novel Treatment Strategies for Porokeratoses: A Narrative Review.

Porokeratoses are a heterogenous group of autoinflammatory keratinization disorders all characterized by the presence of a cornoid lamella. In addition to gene mutations affecting the mevalonate pathway, environmental factors such as UV radiation, immunosuppression, trauma, and infection are also thought to contribute to porokeratoses. To date, there are no management guidelines or levels of evidence for commonly used pharmacologic and non-pharmacologic treatment options for porokeratoses. Conventional treatment strategies encompass topical and systemic drugs (e.g., salicylic acid, topical glucocorticoids, and retinoids), phototherapy, laser, and surgical interventions. Better insights into the pathogenesis of porokeratoses have paved the way for the development of novel therapeutic approaches, such as topical statins or the use of monoclonal antibodies. This narrative review aims to summarize both conventional and novel treatment options, including their level of evidence, advantages, and disadvantages.

Efficacy of an Artificial Intelligence App (Aysa) in Dermatological Diagnosis: Cross-Sectional Analysis.

Dermatology is an ideal specialty for artificial intelligence (AI)-driven image recognition to improve diagnostic accuracy and patient care. Lack of dermatologists in many parts of the world and the high frequency of cutaneous disorders and malignancies highlight the increasing need for AI-aided diagnosis. Although AI-based applications for the identification of dermatological conditions are widely available, research assessing their reliability and accuracy is lacking. The aim of this study was to analyze the efficacy of the Aysa AI app as a preliminary diagnostic tool for various dermatological conditions in a semiurban town in India. This observational cross-sectional study included patients over the age of 2 years who visited the dermatology clinic. Images of lesions from individuals with various skin disorders were uploaded to the app after obtaining informed consent. The app was used to make a patient profile, identify lesion morphology, plot the location on a human model, and answer questions regarding duration and symptoms. The app presented eight differential diagnoses, which were compared with the clinical diagnosis. The model's performance was evaluated using sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and F1-score. Comparison of categorical variables was performed with the χ2 test and statistical significance was considered at P<.05. A total of 700 patients were part of the study. A wide variety of skin conditions were grouped into 12 categories. The AI model had a mean top-1 sensitivity of 71% (95% CI 61.5%-74.3%), top-3 sensitivity of 86.1% (95% CI 83.4%-88.6%), and all-8 sensitivity of 95.1% (95% CI 93.3%-96.6%). The top-1 sensitivities for diagnosis of skin infestations, disorders of keratinization, other inflammatory conditions, and bacterial infections were 85.7%, 85.7%, 82.7%, and 81.8%, respectively. In the case of photodermatoses and malignant tumors, the top-1 sensitivities were 33.3% and 10%, respectively. Each category had a strong correlation between the clinical diagnosis and the probable diagnoses (P<.001). The Aysa app showed promising results in identifying most dermatoses.

An Interesting Case Report of Trichodysplasia Spinulosa in a Case of B-cell Lymphocytic Leukemia

Trichodysplasia spinulosa (TS) is a rare dermatologic condition characterized by follicular-based shiny papules and alopecia with characteristic histopathologic findings. This condition is unique to patients with TS-associated polyoma virus infection who are already immunocompromised. We present one such case of a 10-year-old male, who presented with spiny papules all over the body within a span of 1 month which could not be categorized into any other follicular keratinization disorder on the basis of dermoscopy and histopathology. Our case is unique in the aspect that the patient developed the rash after completion of his chemotherapy. Furthermore, dermoscopy of such a case was not highlighted in earlier literature.

Lid Margin Microbiome in Stevens-Johnson Syndrome Patients With Lid Margin Keratinization and Severe Dry Eye Disease.

The current study evaluated the lid margin microbiome of keratinized lid margins of patients with chronic Stevens-Johnson syndrome (SJS) and compared it with healthy controls and historically reported lid margin microbiome of patients with meibomian gland dysfunction (MGD). Eyelid margin swabs of 20 asymptomatic adults (mean age = 29 ± 12years) and 10 patients with chronic SJS (mean age = 31.2 ± 14years) with lid margin keratinization were sequenced using next generation of 16S rDNA V3 to V4 variable region. Within SJS, the keratinized lid margin microbiome was compared with adjacent eyelid skin. All patients had obstructive MGD, and mean Schirmer I value was 2.8 ± 1.9 mm. The phyla were similar in two groups, whereas at the genera level, an increase in the relative abundance of Corynebacterium, Haemophilus, Azotobacter, and Afipia and a decrease of Acinetobacter was noted in SJS compared to healthy lid margins. SJS-associated microbiota displayed lesser diversity and more heterogeneity than healthy controls. The Principal Components Analysis (PCA) plot revealed wide separation in the SJS and the control groups. Correlational network analysis revealed Corynebacterium and Sphingomonas forming a major hub of negative interactions with other bacterial genera in the SJS group. Significant differences exist in the prevalent genera between keratinized lid margins and historically reported meibum microbiome of patients with MGD. In addition, the eyelid skin of patients with SJS had predominant Staphylococcus, whereas Corynebacterium and Pseudomonas were more in the keratinized lid margins compared to the eyelid skin microbiome. Lid margin microbiome is significantly altered in the keratinized lid margins of patients with SJS compared to the eyelid skin of patients with SJS, normal lid margins, and patients with MGD.

Palmoplantar keratoderma -An Ayurveda Approach

Skin diseases are a major health problem affecting a high proportion of the population in India. Palmoplantar Keratoderma is one of the common disorders of Keratinisation, it is Characterised by a diffuse or focal thickening of the stratum corneum of the palms and soles . All the skin diseases in Ayurveda are broadly classified under the umbrella of kushta .Vipadika is one among the kshudra kushta, characterised by Sphutana and teevra vedana in pani - pada . In the present case -report a patient c/o cracked and dry lessions over both the palms and feet associated with severe itching since 10 months , was treated with oral medicines and external applications respectively. After complete treatment for 3 months there was complete remission in the symptoms and there is no recurrence till date. From the current case report , it can be inferred that Palmoplantar Keratoderma can be treated with the appropriate Ayurveda medications.

Comprehensive Molecular Analysis of Disease-Related Genes as First-Tier Test for Early Diagnosis, Classification, and Management of Patients Affected by Nonsyndromic Ichthyosis.

Inherited ichthyoses are a group of clinically and genetically heterogeneous rare disorders of skin keratinization with overlapping phenotypes. The clinical picture and family history are crucial to formulating the diagnostic hypothesis, but only the identification of the genetic defect allows the correct classification. In the attempt to molecularly classify 17 unrelated Italian patients referred with congenital nonsyndromic ichthyosis, we performed massively parallel sequencing of over 50 ichthyosis-related genes. Genetic data of 300 Italian unaffected subjects were also analyzed to evaluate frequencies of putative disease-causing alleles in our population. For all patients, we identified the molecular cause of the disease. Eight patients were affected by autosomal recessive congenital ichthyosis associated with ALOX12B, NIPAL4, and TGM1 mutations. Three patients had biallelic loss-of-function variants in FLG, whereas 6/11 males were affected by X-linked ichthyosis. Among the 24 different disease-causing alleles we identified, 8 carried novel variants, including a synonymous TGM1 variant that resulted in a splicing defect. Moreover, we generated a priority list of the ichthyosis-related genes that showed a significant number of rare and novel variants in our population. In conclusion, our comprehensive molecular analysis resulted in an effective first-tier test for the early classification of ichthyosis patients. It also expands the genetic, mutational, and phenotypic spectra of inherited ichthyosis and provides new insight into the current understanding of etiologies and epidemiology of this group of rare disorders.

Recalcitrant pityriasis rubra pilaris in a Middle Eastern patient and arguments for early anti‐IL‐23 targeting

AbstractPityriasis rubra pilaris (PRP) is a rare, chronic cutaneous inflammatory disorder of keratinization affecting adults, children and patients with HIV. The pathogenesis of PRP is not fully understood with clinical presentations, and severity remains highly variable. Current treatment modalities for PRP result in recalcitrant disease with potentially unfavourable therapeutic side effects and low tolerability. Due to the rarity of this condition, limited data on treatment efficacies and established management guidelines are lacking. The psychological burden of PRP is detrimental to the quality of life of patients affected with PRP and remains a persistent gap of knowledge. Here, we provide a review of the literature, summarizing new developments in the treatment of PRP and a case report of a patient treated successfully with the anti‐interleukin (IL)‐23p19 antibody Risankizumab with sustained clinical improvement. Risankizumab appears to be an effective and safe treatment for PRP in Asian‐Arabic patients. Further studies are required to assess the efficacy, safety and tolerability of newer targeted therapies for severe PRP.

Symmetrical acrokeratoderma: a case series

Symmetrical acrokeratoderma is rare keratinization disorder which is characterized by symmetrical acral brown to black hyperpigmented keratotic plaques. In this case series, all three patients presented with asymptomatic symmetrical thick raised dark brown skin lesions with rough surface on flexural surface of wrists and dorsum of hands and feet. Palms and soles were spared in all three patients. White maceration and swelling of skin lesions were noticed after soaking in water. All Patients showed good response to oral acitretin and patients were asked for regular follow up every 4 weekly.