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JAMA Dermatology Jul 2023Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and...
IMPORTANCE
Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown.
OBJECTIVE
To determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD.
DESIGN, SETTING, AND PARTICIPANTS
In this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023.
MAIN OUTCOMES AND MEASURES
Comparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue.
RESULTS
Overall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue.
CONCLUSIONS AND RELEVANCE
In this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.
Topics: Aged; Female; Humans; Male; Acantholysis; Darier Disease; Ichthyosis; Retrospective Studies; Sarcoplasmic Reticulum Calcium-Transporting ATPases
PubMed: 37195706
DOI: 10.1001/jamadermatol.2023.1139 -
Vancomycin-Induced Leukocytoclastic Vasculitis: A Rare Complication From a Commonly Used Medication.Cureus Mar 2023Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis that is characterized by the development of a non-blanching palpable purpura. Diagnosis is made...
Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis that is characterized by the development of a non-blanching palpable purpura. Diagnosis is made by skin biopsy and histopathology which shows subepidermal acantholysis with dense neutrophilic infiltrate leading to fibrinoid necrosis of the dermal blood vessels. Etiology is generally idiopathic in most cases but secondary causes include chronic infections, malignancies, systemic autoimmune conditions, and medication use. Treatment involves supportive measures in the case of idiopathic LCV, and treatment of the offending condition or agent in LCV due to a secondary cause. A 59-year-old male presented with purulent ulcers on the plantar surface of the right foot. Radiograph of the right foot showed soft tissue swelling without evidence of osteomyelitis. Empiric antibiotic treatment with vancomycin was initiated. A wound culture was obtained from the purulent drainage which grew positive for methicillin-resistant (MRSA). On the fourth day of treatment with vancomycin, multiple symmetric, purpuric lesions arose on the patient's trunk and extremities. Skin biopsy with histopathology showed subepidermal acantholysis with neutrophil-predominant inflammatory infiltrate consistent with leukocytoclastic vasculitis. Vancomycin was discontinued and the patient's exanthem began to regress, with full resolution after 30 days post withdrawal of the antibiotic.
PubMed: 37102000
DOI: 10.7759/cureus.36532 -
SAGE Open Medical Case Reports 2023Segmental Darier's disease is an uncommon subtype of Darier's genodermatosis, resulting from a mutation in the ATPase type 2 during early embryogenesis. It typically...
Segmental Darier's disease is an uncommon subtype of Darier's genodermatosis, resulting from a mutation in the ATPase type 2 during early embryogenesis. It typically presents as a persistent, pruritic papular eruption following the lines of Blaschko. Histopathology of Darier's disease demonstrates acantholysis, dyskeratosis, and corps ronds. First-line treatment includes topical retinoids, calcineurin inhibitors, and synthetic vitamin D analogues. Severe disease may require systemic therapy with oral retinoids, immunomodulators, magnesium, and low-dose naltrexone. Segmental Darier's disease is important to recognize both clinically and histologically as it may resemble other acantholytic Blaschkolinear dermatoses and should be considered in individuals presenting with a chronic localized papular eruption in a Blaschkoid distribution. Herein, we present a case of a 48-year-old male with segmental Darier's disease who improved significantly following acitretin treatment.
PubMed: 37032996
DOI: 10.1177/2050313X231160938 -
Cancers Mar 2023Histological 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...
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 ( = 54, 48.7%) graded as AK I compared to 35 AKs (31.5%) in the ICG ( = 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 ( < 0.0001). Acantholysis was more frequent in sOTRs than the ICG (59.5% vs. 32.4%, < 0.0001) and more frequently associated with advanced basal proliferation ( < 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.
PubMed: 36980650
DOI: 10.3390/cancers15061765 -
Biology Feb 2023The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of... (Review)
Review
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.
PubMed: 36979046
DOI: 10.3390/biology12030354 -
Acta Dermatovenerologica Croatica : ADC Dec 2022Dowling-Degos disease (DDD) is a benign, rare genodermatosis (reticulate pigmented anomaly) of flexure sites with autosomal dominant inheritance (1,2).The disease is...
Dowling-Degos disease (DDD) is a benign, rare genodermatosis (reticulate pigmented anomaly) of flexure sites with autosomal dominant inheritance (1,2).The disease is caused by a loss-of-function mutation of keratin 5 (KRT5) present on the chromosome 12q gene (3). It usually affects the younger population, most commonly 20-30 years of age, with some patients being older and with a predominance in the female population (4). The disease is characterized by formation of dark, hyperpigmented macules which are confined to the flexure sites, most commonly over the axillae, groin area, and neck, along with scattered, comedo-like lesions and pitted acneiform scars (3,5).The diagnosis is established based on clinical and histopathological correlation. We report the case of a 39-year-old patient who presented with a dark brown discoloration of the skin in the area of vulva, perineum, and perianal region (Figure 1) with occasional itching sensation that had suddenly appeared a year before presentation at our Department. Additionally, sparce brown macules were found in the left axillary region that had appeared a few months earlier. Histopathology of the skin showed fine and irregular elongation of the interpapillary cones with hyperpigmentation. Based on her clinical presentation and histopathology, the diagnosis of DDD was established. The patient was unsuccessfully treated with adapalene gel and refused the recommended oral retinoid therapy, as well as laser therapy. Dowling-Degos disease can present as an isolated disease or can be linked to other clinical entities. Usually, it presents with flat macules which are 3-5 mm in diameter and can vary in color from light brown to black (6). Furthermore, the disease is almost always asymptomatic, but pruritus has been reported in some cases (6), as observed in our patient. Even though DDD is primary a disease of the flexures, there have been reports of patients that have presented with hyperpigmented macules on the dorsum of the hands and feet (7). The affected areas in our patient were the anogenital region and left axillary region, and even though this combination of areas is rather uncommon, to our knowledge two similar cases have been reported in the literature (6,8). The most notable histopathological findings of DDD are elongation of rete ridges of the epidermis as well as hyperpigmentation, usually found in the lower third of the elongated rete ridges (6); both of those features were present in the skin biopsy specimen of our patient. Both the clinical picture and pathohistological findings are crucial for the diagnosis of DDD, and we can conclude that the findings of our patient were consistent with DDD. There are a number of closely related entities to Dowling-Degos disease: Galli-Galli disease (GGD), reticulate acropigmentation of Kitamura (RAPK), Haber disease, and symmetrical acropigmentation of Dohi. Galli-Galli disease has an almost identical clinical presentation, the only difference between those two entities being the presence of acantholysis on biopsy in GGD (9). RAPK presents with hyperpigmentation on the dorsum on the hands and feet, and that pattern has been observed in some patients with DDD as well as GGD (6,7,10-12). However, it differs from DDD in the presence of palmar and plantar pits and slight depression of pigmented lesions (6). Haber disease also has a very similar clinical presentation to DDD, with the presence of dark papules on flexure sites; however, central facial telangiectatic erythema was observed only in Haber disease (13). The clinical features of symmetrical acropigmentation of Dohi are the presence of hyperpigmented macules on the dorsum of the hands and feet, but intermingled areas of hypopigmented macules can also be observed, and the onset of the disease is earlier (infancy and early childhood) when compared with DDD (6,14). There are no successful treatments for DDD. Topical steroids may reduce the itching. Hydroxyquinone, a topical retinoid (adapalene gel), can be used for fading the pigmentation, but there rapid recurrence was reported when treatment was ceased (15). Systemic retinoids have also been unsuccessful. Er:YAG laser treatment has been reported to be effective, but only in a few cases (6,16,17). The goal of this paper was to present the case of a patient with DDD on the vulva, perineum, and perianal region as well as to describe the relationship of DDD with other members of the hyperpigmentative disease family.
Topics: Child, Preschool; Humans; Female; Adult; Perineum; Hyperpigmentation; Pruritus; Retinoids; Adapalene
PubMed: 36919394
DOI: No ID Found -
Modern Pathology : An Official Journal... Jul 2023The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytologic atypia in the squamous epithelium. The conventional grading system of...
The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytologic atypia in the squamous epithelium. The conventional grading system of mild, moderate, and severe dysplasia is considered by many the gold standard in predicting the risk of malignant transformation. Unfortunately, some low-grade lesions, with or without dysplasia, progress to squamous cell carcinoma (SCC) in short periods. As a result, we are proposing a new approach to characterize oral dysplastic lesions that will help identify lesions at high risk for malignant transformation. We included a total of 203 cases of oral epithelial dysplasia, proliferative verrucous leukoplakia, lichenoid, and commonly observed mucosal reactive lesions to evaluate their p53 immunohistochemical (IHC) staining patterns. We identified 4 wild-type patterns, including scattered basal, patchy basal/parabasal, null-like/basal sparing, mid-epithelial/basal sparing, and 3 abnormal p53 patterns, including overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, and null. All cases of lichenoid and reactive lesions exhibited scattered basal or patchy basal/parabasal patterns, whereas human papillomavirus-associated oral epithelial dysplasia demonstrated null-like/basal sparing or mid-epithelial/basal sparing patterns. Of the oral epithelial dysplasia cases, 42.5% (51/120) demonstrated an abnormal p53 IHC pattern. p53 abnormal oral epithelial dysplasia was significantly more likely to progress to invasive SCC when compared to p53 wild-type oral epithelial dysplasia (21.6% vs 0%, P < .0001). Furthermore, p53 abnormal oral epithelial dysplasia was more likely to have dyskeratosis and/or acantholysis (98.0% vs 43.5%, P < .0001). We propose the term p53 abnormal oral epithelial dysplasia to highlight the importance of utilizing p53 IHC stain to recognize lesions that are at high risk of progression to invasive disease, irrespective of the histologic grade, and propose that these lesions should not be graded using the conventional grading system to avoid delayed management.
Topics: Humans; Tumor Suppressor Protein p53; Mouth Neoplasms; Immunohistochemistry; Leukoplakia, Oral; Carcinoma, Squamous Cell; Hyperplasia; Cell Transformation, Neoplastic
PubMed: 36906072
DOI: 10.1016/j.modpat.2023.100153 -
Animal Genetics Aug 2023Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca pump ATP2A2. Defective...
Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine.
Topics: Animals; Dogs; Darier Disease; Mutation, Missense; Heterozygote; Calcium; Pedigree; Dog Diseases
PubMed: 36883421
DOI: 10.1111/age.13314 -
PloS One 2023Inflammatory skin reactions and skin alterations are still a potential side effect in radiation therapy (RT), which also need attention for patients' health care.
BACKGROUND
Inflammatory skin reactions and skin alterations are still a potential side effect in radiation therapy (RT), which also need attention for patients' health care.
METHOD
In a pre-clinical study we consider alterations in irradiated in-vitro skin models of epidermal and dermal layers. Typical dose regimes in radiation therapy are applied for irradiation. For non-invasive imaging and characterization optical coherence tomography (OCT) is used. Histological staining method is additionally applied for comparison and discussion.
RESULTS
Structural features, such as keratinization, modifications in epidermal cell layer thickness and disorder in the layering-as indications for reactions to ionizing radiation and aging-could be observed by means of OCT and confirmed by histology. We were able to recognize known RT induced changes such as hyper-keratosis, acantholysis, and epidermal hyperplasia as well as disruption and/or demarcation of the dermo-epidermal junction.
CONCLUSION
The results may pave the way for OCT to be considered as a possible adjunctive tool to detect and monitor early skin inflammation and side effects of radiotherapy, thus supporting patient healthcare in the future.
Topics: Humans; Tomography, Optical Coherence; Skin; Epidermis; Dermatitis; Keratosis, Actinic; Drug-Related Side Effects and Adverse Reactions
PubMed: 36862637
DOI: 10.1371/journal.pone.0281662 -
Cureus Jan 2023Pemphigus vulgaris (PV) represents damage to epidermal keratinocytes, resulting in acantholysis due to the production of autoantibodies against desmoglein-1 and...
Pemphigus vulgaris (PV) represents damage to epidermal keratinocytes, resulting in acantholysis due to the production of autoantibodies against desmoglein-1 and desmoglein-3. Autoimmune blistering disorders such as pemphigus vulgaris or bullous pemphigoid that develop following coronavirus disease 2019 (COVID-19) have been reported in several studies. Herein, we report a case of PV onset following COVID-19 infection in a 17-year-old female, demonstrating --the potential pathogenic capacity of SARS-CoV-2 to develop PV.
PubMed: 36819405
DOI: 10.7759/cureus.33897