Exploring a Unique Case of Hailey-Hailey Disease: Understanding the Manifestation of Fragile Skin.

Hailey-Hailey disease (HHD) is a rare autosomal dominant chronic blistering disorder. It presents with eruption of small vesicles, erosions, and crusted plaques frequently in the intertriginous areas. Family history is present in some cases. Histopathology plays a crucial role in diagnosing HHD, which is identified by its distinct "dilapidated brick wall" appearance. Due to its uncommon nature and similarity to other skin conditions in intertriginous areas, HHD can often be misdiagnosed by clinicians. We present a case of a 46-year-old female with crusted lesions in the neck, antecubital fossa, submammary folds, and inguinal regions. There were recurrent exacerbations and remissions. Biopsy was sent for histopathological examination, which helped in confirming the diagnosis of HHD.

shRNA-Targeting Caspase-3 Inhibits Cell Detachment Induced by Pemphigus Vulgaris Autoantibodies in HaCaT Cells.

Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease.

A Grover-Like Skin Rash: A Potential Indicator of Underlying Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Transient acantholytic dermatosis, also known as Grover's disease, is an acquired dermatological condition characterised by the sudden emergence of pruritic, erythematous papules, or vesicles, primarily affecting the trunk. It is observed most commonly in men older than 50 years. Histology typically demonstrates a pattern of focal acantholysis within the epidermis, dyskeratotic cells including corps ronds and grains, and a variable perivascular lymphocytic infiltrate in the upper dermis. While its aetiology is not well understood, recognised triggers include excessive heat, sweating, sun exposure, and certain drugs, such as chemotherapy agents. More recently, isolated reports of Grover's disease and Grover-like skin eruptions have been described in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and following COVID-19 vaccination. We report the case of a 65-year-old man who presented to secondary care with a nine-day history of an intensely pruritic rash over his chest and back. On internal medical workup, he was found to have SARS-CoV-2 infection and rapidly deteriorated due to coronavirus disease 2019 (COVID-19)-associated pneumonia, necessitating a 10-day hospital admission for supportive care. Diagnostic workup of his skin lesions confirmed transient acantholytic dermatosis (Grover's disease), which resolved following a course of oral corticosteroids. This case underscores the rare but significant association between Grover's disease and COVID-19, contributing valuable insights to the evolving body of literature on cutaneous lesions associated with SARS-CoV-2 infection, and highlighting the importance of considering SARS-CoV-2 screening as part of the diagnostic workup for patients presenting with Grover-like skin eruptions.

Seborrheic Pemphigus: A Misunderstood Variant of Pemphigus Foliaceus.

Seborrheic pemphigus (SP) represents a localized and superficial form of pemphigus foliaceus (PF) often mistaken for other dermatological conditions such as seborrheic dermatitis (SD) due to clinical similarities. Additionally, SP may be conceptually confused with pemphigus erythematosus (PE) due to historical terminology and overlapping clinical features. We present a case study of a 38-year-old female initially diagnosed with SD but later identified as SP through detailed clinical and histopathological analysis. We discuss the challenges in accurately diagnosing SP, emphasizing the importance of distinguishing it from PE and other acantholytic dermatoses. Furthermore, we highlight the effectiveness of topical treatment in managing SP, contrary to the systemic therapy often required for PE. Our findings underscore the necessity for further research to optimize management strategies for SP and emphasize the significance of precise terminology in clinical practice and research.

Enigma of Acantholytic and Clear Cell Changes in Oral Squamous Cell Carcinoma.

Only limited cases have been reported about the clear cell variant of squamous cell carcinoma occurring in the oral cavity. The present study regards the case showing the histopathological features of both the clear cell and acantholytic variants of oral squamous cell carcinoma. A review of the literature has been done to understand the pathogenesis of those changes. Also, a hypothesis has been given that the clear cell changes could be the consequences of the cascades of the acantholytic process and not a separate entity. Therefore, more research is required to confirm this hypothesis and understand the prognosis of the lesion.

Beyond the Surface: A Clinical Insight Into a 60-Year-Old Male With Pemphigus vulgaris.

Pemphigus vulgaris, a rare and life-threatening autoimmune disorder, presents with painful skin and mucosal lesions, leading to blistering sores attributed to acantholysis. This study delves into the clinical manifestations, risk factors, and diagnostic intricacies associated with pemphigus vulgaris, with a focus on a representative case highlighting the challenges in its recognition and management. We explore the case of a 60-year-old male with pemphigus vulgaris, whose initial presentation involved yellow-crusting lesions on the scalp progressing to non-pruritic lesions on the chest, neck, and inguinal areas. A multidisciplinary medical workup was conducted, encompassing serological tests, imaging, and consultations with infectious disease and dermatology specialists. The definitive diagnosis was established through histopathological examination of three 4-mm punch biopsies. The case underscores the polymorphic nature of pemphigus vulgaris, with diverse clinical presentations and diagnostic challenges. The positive Nikolsky sign on the chest and neck lesions, coupled with oral mucosal involvement observed during a routine dental procedure, exemplifies the complexity of its manifestations. Diagnostic intricacies involved negative results for infectious diseases, declined kidney function, and elevated inflammatory markers, necessitating a collaborative approach for accurate diagnosis. Pemphigus vulgaris demands a comprehensive understanding of its varied presentations and collaboration among medical specialties for accurate diagnosis and tailored management. Treatment involves systemic glucocorticoids and immunomodulators. The presented case underscores the need for continued research to enhance diagnostic accuracy and refine therapeutic interventions for this rare autoimmune disorder.

Corrigendum: Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

[This corrects the article DOI: 10.3389/fimmu.2023.1193032.].

Galli-Galli Disease: A Comprehensive Literature Review.

Galli-Galli disease (GGD) is a rare genodermatosis that exhibits autosomal dominant inheritance with variable penetrance. GGD typically manifests with erythematous macules, papules, and reticulate hyperpigmentation in flexural areas. A distinct atypical variant exists, which features brown macules predominantly on the trunk, lower limbs, and extremities, with a notable absence of the hallmark reticulated hyperpigmentation in flexural areas. This review includes a detailed literature search and examines cases since GGD's first description in 1982. It aims to synthesize the current knowledge on GGD, covering its etiology, clinical presentation, histopathology, diagnosis, and treatment. A significant aspect of this review is the exploration of the genetic, histopathological, and clinical parallels between GGD and Dowling-Degos disease (DDD), which is another rare autosomal dominant genodermatosis, particularly focusing on their shared mutations in the KRT5 and POGLUT1 genes. This supports the hypothesis that GGD and DDD may be different phenotypic expressions of the same pathological condition, although they have traditionally been recognized as separate entities, with suprabasal acantholysis being a distinctive feature of GGD. Lastly, this review discusses the existing treatment approaches, underscoring the absence of established guidelines and the limited effectiveness of various treatments.

Anal involvement in patient with pemphigus vulgaris: Case report.

INTRODUCTION AND IMPORTANCE: Pemphigus Vulgaris (PV) is a low incidence autoimmune mucocutaneous bullous disease, in which pathogenic antibodies are directed against the keratinocyte cell surface. Although anal involvement is unusual, correlations between its appearance and disease severity have been recently reported. CASE PRESENTATION: A 42-year-old male presented with an anal fissure and a year of recurrent oral and pharyngeal aphtha. A chemical sphincterotomy with botulinum toxin plus fissurectomy was performed. 3 years later an upper eyelid injury raised suspicion of pemphigus vulgaris (PV), tested negative for specific antibodies. A couple years later, an anal fissure, and suspected Crohn's disease, led to a second intervention. Surgical analysis unveiled characteristics indicative of a vegetating variant of PV. CLINICAL DISCUSSION: Anal involvement in PV varies in prevalence, with studies reporting rates between 2 % and 27.98 %. This manifestation often accompanies late disease stages and may indicate severity, notably in association with oral lesions. Patients might not readily discuss anal symptoms, leading to potential underreporting. Anal PV is linked to other lesions (ocular, nasal, genital) and the severity of oral PV. Even when other sites are in remission, anal recurrence can occur. Early recognition and follow-up are crucial, highlighting the need for routine anal examination and confirmatory diagnostics. CONCLUSION: PV lesions can present on the skin or mucosa, although oral lesions are the most common site of initial presentation. Anal PV is a diagnostic challenge, and this case illustrates the importance of a careful evaluation.

Tacrolimus reverses pemphigus vulgaris serum-induced depletion of desmoglein in HaCaT cells via inhibition of heat shock protein 27 phosphorylation.

BACKGROUND: Glucocorticoids are the first-line treatment for Pemphigus vulgaris (PV), but its serious side effects can be life-threatening for PV patients. Tacrolimus (FK506) has been reported to have an adjuvant treatment effect against PV. However, the mechanism underlying the inhibitory effect of FK506 on PV-IgG-induced acantholysis is unclear. OBJECTIVE: The objective of this study was to explore the effect of FK506 on desmoglein (Dsg) expression and cell adhesion in an immortalized human keratinocyte cell line (HaCaT cells) stimulated with PV sera. METHODS: A cell culture model of PV was established by stimulating HaCaT cells with 5% PV sera with or without FK506 and clobetasol propionate (CP) treatment. The effects of PV sera on intercellular junctions and protein levels of p38 mitogen-activated protein kinase (p38MAPK), heat shock protein 27 (HSP27), and Dsg were assayed using western blot analysis, immunofluorescence staining, and a keratinocyte dissociation assay. RESULTS: PV sera-induced downregulation of Dsg3 was observed in HaCaT cells and was blocked by FK506 and/or CP. Immunofluorescence staining revealed that linear deposits of Dsg3 on the surface of HaCaT cells in the PV sera group disappeared and were replaced by granular and agglomerated fluorescent particles on the cell surface; however, this effect was reversed by FK506 and/or CP treatment. Furthermore, cell dissociation assays showed that FK506 alone or in combination with CP increased cell adhesion in HaCaT cells and ameliorated loss of cell adhesion induced by PV sera. Additionally, FK506 noticeably decreased the PV serum-induced phosphorylation of HSP 27, but had no effect on p38MAPK phosphorylation. CONCLUSION: FK506 reverses PV-IgG induced-Dsg depletion and desmosomal dissociation in HaCaT cells, and this effect may be obtained by inhibiting HSP27 phosphorylation.

Diagnosis and management of vulvar Darier disease: A case report.

Darier disease is an autosomal dominant disorder with hyperkeratotic papules affecting primarily seborrheic areas of the upper chest, back, forehead, scalp, nasolabial folds, ears, and, less frequently, the oral mucosa. A typical eruption consists of keratotic and crusted skin-colored papules and plaques. Pruritus occurs in 80% of patients, and pain is rare. Lesions can be triggered by exposure to ultraviolet light, heat, or stress. Secondary infections of the lesions are a common complication. A definitive diagnosis is obtained by a biopsy showing histological features such as acantholysis, suprabasal clefts, and "corps rond and grains". Here we present a 37-year-old woman admitted to the gynecology department with pruritic lesions she had noticed on her vulva and perineum for three months. A vulvar biopsy led to the diagnosis of Darier disease. She was referred to the dermatology department and treated with oral acitretin since systemic retinoids are offered as the first-line treatment of the disease.

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of in vitro and in vivo evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis in vitro, as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients' autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting.

Pénfigo foliáceo, variedad seborreica, reporte de caso / Pemphigus foliaceus, seborrheic variety, case report

Presentación del caso. Se expone el caso de un paciente masculino de 48 años de edad, sin antecedentes médicos conocidos, que presentó múltiples lesiones en forma de placas eritematocostrosas fácilmente descamativas, inicialmente en tórax anterior, que se esparcían sobre el rostro y cuero cabelludo sin afectar las mucosas. Intervención terapéutica. El manejo hospitalario se basó fundamentalmente en el uso de esteroides tópicos y sistémicos, así como el manejo de las infecciones sobreagregadas a las lesiones dermatológicas y el apoyo psicológico del paciente. Se tomó biopsia de piel donde se evidenció la presencia de acantólisis, confirmando el diagnóstico de esta enfermedad autoinmunitaria. Evolución clínica. Luego del tratamiento se logró una reducción de las múltiples lesiones descamativas, el control de la infección local y la recuperación de la piel del paciente, la cual a pesar de aún presentar cicatrices se encontraba con sus funciones restituidas

Case presentation. a 48-year-old male with no known medical history who presented multiple lesions in the form of easily desquamative erythematous and crusted plaques, initially on the anterior thorax, which spread over the face and scalp without affecting the mucous membranes. Treatment. In-hospital management was mainly based on topical and systemic steroids, the management of infections superadded to the dermatologic lesions, and psychological support for the patient. A skin biopsy was taken where acantholysis was evidenced, confirming the autoimmune disease diagnosis. Outcome.After treatment, the multiple scaly lesions were reduced, the local infection was controlled, and the patient's skin recovered although it still had scars, its functions were restored

Histopathological characterisation of trunk-dominant canine pemphigus foliaceus, and comparison with classic facial and insecticide-triggered forms.

BACKGROUND: While the clinical features were described recently, the histopathological characterisation of trunk-dominant canine pemphigus foliaceus (PF) is lacking, and whether it differs from classic facial or insecticide-triggered PF is unknown. HYPOTHESIS/OBJECTIVES: This study describes the histopathological findings of trunk-dominant PF, and compares the results to classic facial and insecticide-triggered PF. ANIMALS: Skin biopsies from 103 dogs with clinically characterised trunk-dominant (n = 33), classic facial (n = 26) and insecticide-triggered PF (n = 44) were included. MATERIALS AND METHODS: Histological sections, randomised and blinded, were scored for over 50 morphological parameters of pustules, epidermis, dermis, adnexa and crusts. Intact pustule area and width were measured by digital microscopy. RESULTS: In trunk-dominant PF, 77 intact pustules were predominantly subcorneal (0.0019-1.940 mm2 area, 0.0470-4.2532 mm wide), and contained from one to over 100 acantholytic keratinocytes. Pustules had boat acantholytic cells, corneocytes, perinuclear eosinophilic rings, neutrophil rosettes, acantholytic cell necrosis, rafts, cling-ons and/or eosinophils. Peripustular epidermal spongiosis, necrosis and lymphocyte exocytosis occurred, as did follicular pustules. Mixed dermal inflammation often contained eosinophils. Trunk-dominant PF did not differ from the other PF groups except for few parameters, such as having fewer rafts (p = 0.003). Additional autoimmune inflammatory patterns occurred in all PF groups. CONCLUSIONS AND CLINICAL RELEVANCE: Trunk-dominant PF and other canine PF variants are histologically similar, which indicates shared pathomechanisms. The identification of common boat acantholytic cells and corneocyte separation has implications for the mechanisms of acantholysis. The diversity of histopathological and polyautoimmunity features support complicated immune mechanisms. Finally, results indicate that diagnostic biopsies cannot differentiate between these PF variants in dogs.

The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris.

The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease.

Basal Proliferation and Acantholysis May Represent Histological High-Risk Factors for Progression into Invasive Squamous Cell Carcinoma: A Comparison Study in Solid Organ Transplant Recipients and Matched Immunocompetent Patients.

Histological risk factors of AKs cannot be directly determined. Recent studies indicate that AKs restricted to the lower third of the epidermis (AK I), with marked basal proliferation (PRO III) and acantholysis, are associated with an increased risk of progression to invasive squamous cell carcinoma (iSCC). To confirm the aforementioned histological risk factors, this study compared AKs from solid organ transplant recipients (sOTRs), known to carry an up to 250-fold higher risk for progression into iSCC, to a matched immunocompetent control group (ICG). In total, 111 AKs from 43 sOTRs showed more AKs (n = 54, 48.7%) graded as AK I compared to 35 AKs (31.5%) in the ICG (p = 0.009). In line with these findings, 89 AKs (80.2%) from sOTRs showed pronounced basal proliferation (PRO III) compared to 37 AKs (33.3%) in the ICG (p < 0.0001). Acantholysis was more frequent in sOTRs than the ICG (59.5% vs. 32.4%, p < 0.0001) and more frequently associated with advanced basal proliferation (p < 0.0001). In conclusion, this study showed that acantholytic AKs graded as AK I and PRO III are predominantly found in a population at high risk of iSCC. Thus, AKs with marked basal proliferation and acantholysis should be assumed to be histological high-risk factors for the progression into iSCC.

Post-Pemphigus Acanthomata Presenting as an Isolated, Hyperkeratotic Plaque.

Post-pemphigus acanthomas have been rarely discussed in the literature. A prior case series identified 47 cases of pemphigus vulgaris and 5 cases of pemphigus foliaceus, out of which 13 developed acanthomata as a part of the healing process. Additionally, a case report by Ohashi et al. reported similar recalcitrant lesions on the trunk of a patient with pemphigus foliaceus being treated with prednisolone, IVIG, plasma exchange, and cyclosporine. Some view post-pemphigus acanthomas as variants of hypertrophic pemphigus vulgaris, being difficult to diagnose when they present as only single lesions, with a clinical differential of an inflamed seborrheic keratosis or squamous cell carcinoma. Here, we present a case of a 52-year-old female with a history of pemphigus vulgaris and four months of only topical therapy (fluocinonide 0.05%) who presented with a painful, hyperkeratotic plaque on the right mid-back that was found to be a post-pemphigus acanthoma.

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

A Case Report on Senear-Usher Syndrome.

Pemphigus erythematosus is an uncommon autoimmune bullous skin disorder with clinical, histological, and serological characteristics that overlap with lupus erythematosus and pemphigus foliaceus. The autoantigens are desmoglein 3, desmoglein 1, and desmosomal adhesion proteins in keratinocytes. When these bonds are disrupted, it causes acantholysis of keratinocytes, leading to the fluid collection between layers. Hence, the patient will present clinically with small flaccid bullae with crusting and scaling, mainly on the seborrheic areas. We report the case of a 21-year-old female presenting to us with multiple hyperkeratotic plaques, mainly on the seborrheic areas, including the face, chest, and elbows. The patient was evaluated further, and based on clinical and laboratory investigations, the diagnosis of pemphigus erythematosus associated with anti-double-stranded deoxyribonucleic acid (anti-dSDNA) and anti-nuclear antibody (ANA) positivity was made. The patient was then managed using immunosuppressant therapy, and the entire course has been detailed in this case report.

Lichenoid lesions around the anus: An unusual site of Hailey-Hailey disease.

The anal region is an unusual site of Hailey-Hailey disease. It manifests with lichenoid lesions with crusted erosions around the anus. It should be differentiated from condylomata acuminata, extramammary Paget disease, and bowenoid papulosis.