Proliferative Skin Disease Research Articles

The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.

A Comparative Study on the Effect of Vidangadi Lepa and Jeevantyadi Lepa in Eka Kushta w.s.r. to Psoriasis

Psoriasis is a chronic inflammatory and hyper proliferative skin disease. It is characterized by well-defined, erythematous scaly papules affecting about 0.1% to 3% of the population. Psoriasis can be correlated to Ekakushta which is Kapha-vata predominant. It presents with Aswedana, Mahavasthu and Matsya Shakalopama and is treated with Shodhana Karma and Bahya Chikista including Lepa Karma that occupies the prime place in its line of treatment. Acharyas have mentioned different types of Lepas and its effectiveness in skin disorders. Objective of study: To study the effect of Jeevantyadi Lepa and Vidangadi Lepa in Ekakushta and to compare its therapeutic effects in the management of Ekakushta w.s.r. to psoriasis Methods: This is a comparative clinical study with pre-test and post-test design that included 40 patients of either sex diagnosed as Ekakusta (psoriasis). All the 40 patients were randomly assigned into 2 groups with 20 patients in each. The procedure in group A involves application of Vidangadi Lepa and group B involves application of Jeevantyadi Lepa. Results: The overall results in the study revealed the statistically significant results in Group A and in Group B on all subjective and objective parameters. Conclusions: Group A and Group B had shown significant results but however Group A had an edge over to Group B.

Formulation characterization of lecithin organogel as topical drug delivery system for psoriasis: In-vitro permeation and preclinical evaluation.

Psoriasis is a chronic inflammatory and proliferative skin disease that causes pathological skin changes and has a substantial impact on the quality of patient life. Apremilast was approved by the US Food and Drug Administration as an oral medication for psoriasis and is beneficial in mild to moderate conditions for chronic usage. However, 5%-7% of withdrawals were reported due to severe side effects. To address the issue, a localized drug delivery strategy via the topical route may be a viable approach. However, poor physicochemical properties make it vulnerable to passing through the skin, requiring a specialized drug delivery system to demonstrate its full potential via a topical route like lecithin organogel. The formulation was optimized by screening the suitable lecithin type and non-polar solvents based on the gel formation ability of lecithin and the solubility of apremilast in the solvent. The pseudo-ternary diagram was used to optimize the water content required to form the gel. The optimized gel was found to be shear thinning characterized for rheological parameters, in-vitro diffusion studies, and in-vitro skin distribution studies. Preclinical studies in Imiquimod-induced mice showed a better reduction in severity index, cytokine levels, and epidermal hyperplasia from the lecithin organogel group compared to the apremilast oral administration and marketed standard topical gel group. Based on these results, lecithin organogel can be considered a promising approach to deliver molecules like apremilast by topical route in psoriatic-like conditions.

A Case Study Using Chirabilva as a Single Drug Remedy to Manage Kitibha Kushta

Introduction: Kitibha is a skin disease, explained in Ayurveda under the broad term kushta. It is characterized by shyava, kinakharasparsha, parusha, and khandu. It can be correlated with psoriasis based on clinical features. Psoriasis is a proliferative autoimmune skin disease. About 2-3% of the population have psoriasis according to the World Psoriasis Day Consortium. Materials and Methods: Chirabilva Kashaya internally and Chirabilva Taila externally were advised for the patient diagnosed as Kitibha Kushta for 30 days and assessment done before treatment, after treatment, and after follow-up. Discussion: The drug Chirabilva having the Kustahara, Lekhaniya, Bhedaniya, and Krimihara properties was selected for the treatment of Kitibha Kushta and it was administered both internally and externally in kashaya and taila form, respectively, to study the effectiveness of single drug in Kitibha Kushta of recent origin. Conclusion: Chirabilva as a single drug when given internally and externally relieved the symptoms, so in acute cases even without panchakarma single drug can be effective in managing the disease.

Ayurvedic management of Psoriasis (Kitibha) - A Case Report

Psoriasis is a chronic disorder which is commonly encountered in day-to-day clinical practice. It is a chronic non-communicable proliferative autoimmune skin disease which affects 2-3% of worldwide population. Psoriasis is a disorder of hyperkeratinisation characterized by sharply defined erythemato-squamous lesions. WHO considers skin diseases as Psycho-cutaneous diseases. Psoriasis has resemblance with Kitibha Kushta in Ayurveda. Kitibha Kushta is one of the Kshudra Kushta, characterized by skin manifestation having the symptoms Shyava Varna (blackish brown discoloration), Kinakhara Sparsha (rough in touch), Parushatva (hard) and Kandu (itching). Due to Bahudosha involvement, Shodhana (purifying therapy) followed by Shamana (palliative therapy) plays an important role in the management of Kushta. Case Summary: A 35 years old male patient approached with the complaints of diffuse scaly lesions over scalp, bilateral upper and lower limbs, abdomen and back associated with itching and powdery appearance since 8 years. He was diagnosis with Psoriasis (Kitibha) on the basis of signs and symptoms. The patient was given with Deepana, Pachana, Virechana, Kushtahara Shamana Aushadis (Oral medications) and Kumarabharana Rasa as line of management. Significant improvement was observed after 1 month of treatment in terms of PASI Score.

Association of body mass index with clinical variants of psoriasis

Introduction/Aim. Psoriasis is a common, chronic, immune-mediated, inflammatory and proliferative skin disease in which both genetic and environmental influences have a role in its pathogenesis. The relationship between psoriasis and obesity is probably bidirectional. The aim of this study was to evaluate the association between psoriasis and obesity, whether a quantitative graduation of overweight using Body Mass Index (BMI) shows direct correlation with various clinical variants of psoriasis, disease duration and having positive family history of psoriasis. Methods. This prospective, observational descriptive cross-sectional study included 120 psoriatic patients who were referred to Clinic of Dermatovenereology at the University Clinical Centre of Vojvodina. Clinical variants of psoriasis were determined. Age, gender, duration of the disease, BMI and family history of psoriasis were measured and compared. Results. In total, 53.3% males and 46.7% females were included in this study. The mean age was 49.5 ? 15.5 years. The most present clinical variants of psoriasis were psoriasis vulgaris (55%) and psoriatic arthritis (30%). Most of the patients (42.5%) were overweight, 23.3% were obese, and 1.7% were morbidly obese. The mean BMI was high (27.7 ? 5.2). Mean duration of the disease was 15.6 ? 14.9 years. Positive family history of psoriasis was found in 33 (27.5%) patients. Conclusion. There was no correlation between the BMI and gender of the patients, psoriasis clinical variants, duration of the disease and positive family history of psoriasis. The slight positive correlation was found between BMI and age of psoriatic patients. That requires further studies that include physical activities questionnaire, considering that lack of physical activities in older patients might be an explanation.

Perillyl alcohol inhibits keratinocyte proliferation and attenuates imiquimod-induced psoriasis like skin-inflammation by modulating NF-κB and STAT3 signaling pathways

Psoriasis is a chronic inflammatory and proliferative skin disease characterized by pathological skin lesions which significantly impact the quality of life. Recent studies have been proven that inhibitors of farnesyltransferase enzyme showed significant anti-psoriatic activity. Perillyl alcohol (POH) is one such natural molecule having anti proliferative, anti-inflammatory and anti-oxidant properties by inhibiting farnesyltransferase enzyme which further down regulates NF-κB and STAT3 via Ras/Raf/MAPK pathway. Hence, in the current study we aimed to find the effect of POH on human keratinocytes (HaCat) cells in in-vitro and IMQ induced psoriatic like skin inflammation model in mice. POH significantly decreased the intracellular ROS levels and inhibited the phosphorylation of NF-κB and STAT3 in in-vitro. It was found that POH (200 mg/kg, topical application) has reduced the epidermal hyperplasia, psoriasis area and severity index (PASI) scoring; splenomegaly in imiquimod (IMQ) induced psoriatic mice. Further, POH treatment has decreased the pro-inflammatory serum cytokine levels such as IL-6, IL-12/23, TNF-α and IL-1β and also reduced the expression levels of various inflammatory proteins, COX-2, iNOS, IL-17A, IL-22, NF-кB and STAT3 evidenced by Immunoblotting studies from skin samples. The levels of endogenous antioxidants like glutathione GSH, SOD, Nrf2 were restored to normal levels upon POH treatment. POH downregulated the proteins levels of TLR7, TLR8, CyclinD1 and mRNA expression of Bcl-2 in the skin samples when compared to the IMQ group. POH has ameliorated the hyper-keratosis and acanthosis which was evidenced by histopathology. Collectively, our results suggest that POH has a promising therapeutic application for ameliorating psoriasis-like skin inflammation.

Implications of narrowband ultraviolet B treatment on psoriasis severity and serum levels of angiopoietin-2: A cross-sectional controlled study.

Psoriasis is a chronic inflammatory hyper proliferative skin disease. Angiogenesis play an important role in Psoriasis pathogenesis, occurring even before plaque formation. Angiopoietins play an important role in angiogenesis and hence are described as angiogenic factors. To evaluate serum levels of angiopoeitin 2 (Ang-2) following treatment with narrowband ultraviolet B (NBUVB) in patients with moderate-severe plaque psoriasis and correlate it to psoriasis area and severity index (PASI). This cross sectional study included 38 patients complaining of moderate to severe plaque psoriasis and 38 healthy controls. Psoriasis area and severity index (PASI) was determined and was correlated to serum levels of Ang-2 before and after treatment with NBUVB. PASI scores and serum values of angiopoietin 2 demonstrated a significant difference between the baseline and at the end of the 12weeks NBUVB treatment. A statistically significant positive correlation was established between psoriasis severity and Ang-2 serum levels before and after treatment. The study demonstrated a potential contribution of Ang-2 in the pathogenesis of psoriasis, as well as its usefulness as a biomarker of psoriasis severity.

Bath Psoralen Plus UVA Therapy Suppresses Keratinocyte-Derived Chemokines in Pathogenetically Relevant Cells

Psoriasis is a chronic inflammatory proliferative skin disease involving various types of chemokines regulating immune cell migration, localization, and activation. Bath psoralen plus UVA (PUVA) treatment is an established phototherapy for psoriasis, but its effects on chemokine levels remain unknown. We investigated the levels of 22 serum chemokines in 20 patients with psoriasis first treated with bath PUVA therapy between 2007 and 2011 in a single center and analyzed the associations between the chemokines and disease severity (PASI) before and after therapy to investigate the mechanisms of action of bath PUVA therapy. Before bath PUVA therapy, the PASI scores correlated with the serum levels of CCL17 (r = 0.581), CCL18 (r = 0.462), CCL19 (r = 0.477), and CXCL16 (r = 0.524). After bath PUVA, the serum levels of CCL17, CCL22, CXCL1, and CXCL9 were significantly decreased. Heatmap clustering and network analysis based on statistically significant Spearman correlations among the chemokines showed distinctive changes in the chemokine signature. Our findings revealed that the levels of several chemokines correlated with the disease state of psoriasis. Furthermore, bath PUVA therapy reduced the secretion of keratinocyte-derived chemokines that induce the migration of immune cells important for psoriasis pathogenesis, partly revealing the mechanism of the therapeutic activity.

Herpesvirus-Associated Proliferative Skin Disease in Frogs and Toads: Proposed Pathogenesis.

A comparative study was carried out on common and agile frogs (Rana temporaria and R. dalmatina) naturally infected with ranid herpesvirus 3 (RaHV3) and common toads (Bufo bufo) naturally infected with bufonid herpesvirus 1 (BfHV1) to investigate common pathogenetic pathways and molecular mechanisms based on macroscopic, microscopic, and ultrastructural pathology as well as evaluation of gene expression. Careful examination of the tissue changes, supported by in situ hybridization, at different stages of development in 6 frogs and 14 toads revealed that the skin lesions are likely transient, and part of a tissue cycle necessary for viral replication in the infected hosts. Transcriptomic analysis, carried out on 2 naturally infected and 2 naïve common frogs (Rana temporaria) and 2 naturally infected and 2 naïve common toads (Bufo bufo), revealed altered expression of genes involved in signaling and cell remodeling in diseased animals. Finally, virus transcriptomics revealed that both RaHV3 and BfHV1 had relatively high expression of a putative immunomodulating gene predicted to encode a decoy receptor for tumor necrosis factor in the skin of the infected hosts. Thus, the comparable lesions in infected frogs and toads appear to reflect a concerted epidermal and viral cycle, with presumptive involvement of signaling and gene remodeling host and immunomodulatory viral genes.

Management of Kitibha Kustha (Psoriasis) - A case report

In Ayurveda all the skin disease is kept under the topic “kustha roga”. Kitibha kustha is one of the kustha roga in which the skin becomes dull black, rough, dry like scar. It is vitiated by vata and kapha doshas. It can be clinically correlated with psoriasis in modern science. Psoriasis is the chronic inflammatory and hyper proliferative skin disease. Here, in the case a male patient of 42 years came with complain of scaly lesion all over the body since 32 years. Lesion was associated with itching and aggravated in winter season. The patient was clinically diagnosed with Kitibha Khustha (psoriasis). For the case sodhana and samana chikitsa was done. Patient got relief with in the treatment of 45days. Through the case it can be concluded that kitibha kusth can be cured by following the treatment protocol of Ayurveda.

Recent developments in trichodysplasia spinulosa disease.

Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is characterized by uncontrolled inner root sheath cell proliferation and folliculocentric papular eruption that can progress to disfiguring leonine facies when left untreated. TS presents with distinct histological features including the presence of large eosinophilic, trichohyaline granules within hyperproliferating inner root sheath cells of the hair bulb. The discovery of the Trichodysplasia Spinulosa Polyomavirus (TSPyV) and recent studies highlighting the role of TSPyV tumor antigens in cell proliferation pathways have provided new insight into the mechanisms of TS development. In this review, we discuss the expansion of our understanding of TS, specifically over the past 5years. We summarize novel cases of TS and recent developments in the mechanisms underlying TSPyV-mediated disease progression. We also evaluate advancements in diagnostic methods and treatment options. As the incidence of TS continues to rise, it is becoming critical for clinicians to understand the clinical features of TS and emerging research regarding pathogenesis and therapeutics for early treatment of this potentially disfiguring disease.

Ayurvedic Management of Kitibha Kushta (Psoriasis) - A Case Study

All the skin diseases in Ayurveda have been discussed under the broad heading of“Kustha”. Psoriasis is a proliferative autoimmune skin disease which is affecting 2% of worldwide population. In India, overall incidence of Psoriasis among total patients attending skin OPD is 0.28 to 0.44%. This disease characterised by scaling, thickened-rough skin lesions, itching, in severe cases covers entire body. Modern medical science treats psoriasis with Psoralen and Ultraviolet therapy (PUVA). But the disease has high recurrence rate and the modern medications have serious side effects like liver failure, renal failure, and bone marrow depletion etc. Here, Ayurveda treatment is under taken to provide safe and effective remedy for psoriasis. Present case report of 56 year old male patient having severe psoriasis (Kitibha Kusta) showed encouraging result after Virechana Karma and Shamana Chikitsa.

Risk and severity of psoriasis vulgaris in relation to angiotensin II type 1 receptor gene polymorphism and metabolic syndrome.

BackgroundPsoriasis vulgaris is a chronic inflammatory and proliferative skin disease, characterized by the formation of itchy, erythematous skin patches or plaques. Patients with psoriasis are at an increased risk of developing metabolic syndrome, including obesity, hypertension, diabetes, and atherosclerosis. Recently, angiotensin II (Ang II) has been reported to be associated with the development of psoriasis. Ang II not only increases the blood pressure but is also a potent proinflammatory modulator and functions through interaction with angiotensin II type 1 receptor (AT1R). Moreover, it is hypothesized that the AT1R gene expression could be correlated with the severity of psoriasis and/or metabolic syndrome.AimWe examined the association of Ang II type 1 receptor (AT1R) A1166C gene polymorphisms and metabolic syndrome with the severity of psoriasis.Patients and methodsThe present case-control study included 25 patients with psoriasis vulgaris and 25 healthy subjects in Egypt. The psoriasis lesions in the patient group were assessed using the psoriasis area and severity index (PASI) score. The AT1R polymorphism A1166C (rs5186) was studied using restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) amplification of the gene from the whole blood sample in both groups. Serum lipid profile and blood sugar levels were assessed post 12 h and 8 h fasting, respectively, in both groups. The severity of metabolic syndrome was evaluated using the severity score.ResultsThe results of the present study demonstrated that the AT1R A1166C gene polymorphisms increased the risk of developing psoriasis in the Egyptian population. We found that 70% of patients with AC genotype and 100% of patients CC genotype reported a PASI score >20 and were considered to be severe cases with a statistically significant difference as compared with patients with AA genotype (p=0.003). In addition, a high statistically significant difference (p=0.001) existed among AT1R genotypes with respect to the percentage of metabolic syndrome in psoriasis patients. Similarly, a statistically significant difference (p=0.004) among AT1R genotypes with respect to metabolic score was found, with the highest level of score and percentage observed in patients with CC genotype than in patients with AC genotype. The lowest level was present among those with AA genotype.ConclusionPatients with psoriasis expressing the C allele of AT1R1166 are susceptible to developing metabolic syndrome and have higher PASI scores as compared with patients carrying the A allele.

Are new variants of psoriasis therapy (IL‐17 inhibitors) safe?

Psoriasis is a chronic, recurrent, inflammatory, and proliferative skin disease. Its etiology has not yet been fully assessed, but undoubtedly it is a multifaceted disease. The key role in its pathomechanism is played by genetic, immunologic, and environmental factors and stress. If traditional methods of psoriasis treatment (phototherapy, methotrexate, retinoids, cyclosporine A) fail, we reach for the following biopharmaceuticals - infliximab, etanercept, adalimumab, or ustekinumab. However, genetic engineering progress discovers new possibilities - the pending clinical trials involve IL-17, IL-23 antagonists, PDE4 and -3 and -1. Psoriasis etiopathogenesis mainly involves the IL-17A, IL-17F, and IL-17A/F subtypes, which affect the keratinocytes. The biological therapy molecularly oriented with the antagonists of interleukin 17 is based mainly on the influence onto the cytokine in the manner that prevents it from binding with the receptor. Three biopharmaceuticals are currently under third phase studies: two fully humanized antibodies neutralizing IL-17 - ixekizumab and secukinumab, and one human monoclonal antibody, brodalumab. The below work will be devoted to the analysis of possible undesirable symptoms, which were observed during the studies. We will try to review the latest literature concerning the most important clinical trials conducted in many centers.

A Study of Non Melanoma Skin Cancers Occuring Over the Psoriatic Plaque

This study attempts to find out the incidence of non melanoma skin cancers in psoriasis patients. Psoriasis is a chronic, relapsing, inflammatory and proliferative skin disease associated with cutaneous and systemic diseases.

A study on status of homocysteine in psoriasis patients

Psoriasis is a chronic inflammatory, proliferative skin disease characterized by pathological skin lesions due to various exogenous and endogenous factors. It is associated with a number of biochemical and immunological disturbances. Recently, it has been suggested that increased reactive oxygen species (ROS) production and compromised function of antioxidant system may be involved in the pathogenesis of this disease. This study intends to assess and compare the levels of HCY and MDA amongst the cases and healthy controls. In the present study, total of 100 subjects, among them 25 psoriasis patients were selected. Serum levels of malondialdehyde and Homocysteine levels were increased in psoriasis as compared to controls. We found severity wise significantly increased serum malondialdehyde and HCY status in patients with psoriasis. Our results indicate that, in psoriasis patients with increased oxidative stress there is increased Homocysteine levels. In conclusion, Homocysteine could serve as a biomarker of psoriasis severity but not as a marker of psoriasis.

Production and characterization of monoclonal antibodies specific for major capsid VP1 protein of trichodysplasia spinulosa-associated polyomavirus.

Trichodysplasia spinulosa-associated polyomavirus (TSPyV), a newly identified polyomavirus, has been implicated as a causative agent of trychodysplasia spinulosa (TS), a rare proliferative skin disease in severely immunocompromised hosts. Diagnosis using mAbs is a promising tool with high specificity towards the specific antigen. However, thus far, no suitable mAbs for diagnosing TS disease have been identified. In this study, mAbs specific for VP1 of TSPyV were developed and characterized. Wheat germ cell-free synthesized VP1 protein of TSPyV was used to immunize BALB/c mice to generate hybridomas. Screening of the resultant hybridoma clones resulted in selection of five strongly positive clones that produce mAbs that react with the TSPyV-VP1 antigen. Epitope mapping and bioinformatic analysis showed that these mAbs recognized epitopes located within highly conserved C-terminal region of all clinical isolates of TSPyV-VP1. Further, all these mAbs were highly effective for immunofluorescence and immunoprecipitation analysis. Three of the five mAbs exhibited no cross-reactivity with VP1 of other related polyomaviruses. In addition, one of our mAbs (#14) provided immunohistochemical staining of skin tissue of TS disease. It can be concluded that three of the mAbs in this panel of anti-VP1 antibodies may provide a useful set of tools for studying TSPyV infection and making the specific diagnosis.

Nobiletin and 5-Hydroxy-6,7,8,3',4'-pentamethoxyflavone Ameliorate 12- O-Tetradecanoylphorbol-13-acetate-Induced Psoriasis-Like Mouse Skin Lesions by Regulating the Expression of Ki-67 and Proliferating Cell Nuclear Antigen and the Differentiation of CD4+ T Cells through Mitogen-Activated Protein Kinase Signaling Pathways.

Psoriasis is a chronic and benign proliferative skin disease. Flavonoids in chenpi (aged tangerine peel) from tangerine ( Citrus reticulate Blanco), such as nobiletin (Nob), tangeretin, and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF), possess anti-inflammation and regulation of immune activity among others. In this study, psoriasis-like skin lesions were induced by 12- O-tetradecanoylphorbol-13-acetate (TPA), and the preventive effect of Nob and 5-HPMF on psoriasis-like skin lesions was evaluated. Results showed that skin lesions were dramatically reduced by Nob and 5-HPMF. Levels of cytokines, including interleukin (IL)-1β, IL-17, IL-4, IL-6, tumor necrosis factor-α, and interferon-γ, were also reduced after Nob and 5-HPMF treatment. The expression levels of p-ERK1/2 and p-p38 mitogen-activated protein kinase (MAPK) in the TPA group were 5.3, 4.8, and 5.7 but downregulated to 2.7, 2.9, and 2.3 in the Nob group and 2.4, 2.7, and 1.2 in the 5-HPMF group, respectively ( p ≤ 0.05). The expression of transcription factors Ki-67 and proliferating cell nuclear antigen (PCNA) and the differentiation of CD4+ T cells were reduced by downregulating the expression of the MAPK signaling pathways. The expression levels in TPA, Nob, and 5-HPMF groups were 0.649 ± 0.094, 0.218 ± 0.034, and 0.193 ± 0.042 for Ki-67 and 0.753 ± 0.114, 0.315 ± 0.094, and 0.294 ± 0.035 for PCNA, respectively. Moreover, 5-HPMF showed stronger reduction activity in the prevention of psoriasis than Nob, indicating that the 5-hydroxyl group facilitated the suppression of psoriasis.

RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models?

Tylosis with esophageal cancer syndrome (TOC) is a rare autosomal dominant proliferative skin disease caused by missense mutations in the rhomboid 5 homolog 2 (RHBDF2) gene. TOC is characterized by thickening of the skin in the palms and feet and is strongly linked with the development of esophageal squamous cell carcinoma. Murine models of human diseases have been valuable tools for investigating the underlying genetic and molecular mechanisms of a broad range of diseases. Although current mouse models do not fully recapitulate all aspects of human TOC, and the molecular mechanisms underlying TOC are still emerging, the available mouse models exhibit several key aspects of the disease, including a proliferative skin phenotype, a rapid wound healing phenotype, susceptibility to epithelial cancer, and aberrant epidermal growth factor receptor (EGFR) signaling. Furthermore, we and other investigators have used these models to generate new insights into the causes and progression of TOC, including findings suggesting a tissue-specific role of the RHBDF2-EGFR pathway, rather than a role of the immune system, in mediating TOC; and indicating that amphiregulin, an EGFR ligand, is a functional driver of the disease. This review highlights the mouse models of TOC available to researchers for use in investigating the disease mechanisms and possible therapies, and the significance of genetic modifiers of the disease identified in these models in delineating the underlying molecular mechanisms.