OTULIN-related conditions: Report of a new case and review of the literature using GenIA.

OTULIN encodes an eponymous linear deubiquitinase (DUB) essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway via the regulation of M1-Ub dynamics. Biallelic loss-of-function (LOF) mutations in OTULIN cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic OTULIN LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative (DN) effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595 T > A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype and provide experimental evidence for its pathogenicity. We go on to systematically review the literature for OTULIN-associated conditions by using the GenIA database (www.geniadb.net) to collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the OTULIN pathogenic variants may lead to human immune disease. This review may help variant classification activities and inform future variant evaluation, as well as the development of diagnostic and management guidelines. It also identifies current knowledge gaps and raises additional questions warranting future investigation.

OTULIN-related conditions: Report of a new case and review of the literature using GenIA.

OTULIN encodes an eponymous linear deubiquitinase (DUB), which through the regulation of M1-Ub dynamics, is essential for controlling inflammation as a negative regulator of the canonical NF-κB signaling pathway. Biallelic loss-of-function (LOF) mutations in OTULIN cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic OTULIN LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595T>A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype. We go on to systematically review the literature for OTULIN-related human disease phenotypes by using the GenIA database to collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the OTULIN pathogenic variants may lead to human immune disease. This review may help variant classification activities and the drafting of diagnostic and management guidelines; but it also identifies outstanding knowledge gaps and raises additional questions for future investigation.

Orbea variegata (L.) Haw in skin carcinogenesis: insights from an in vivo male Swiss mouse model study.

Skin cancer is the most widespread type of malignant tumor representing a major public health concern. Considering the numerous side effects associated with conventional treatments, phytotherapy may be regarded as a viable medicinal alternative. This study aimed to investigate the therapeutic potential of Orbea variegata (L.) Haw, an ornamental plant, in treating skin cancer using an animal model induced by a combination of ultraviolet (UV) irradiation and sulfuric acid treatment. The hydroethanolic extract of Orbea variegata underwent phytochemical characterization, identifying the presence of reducing sugars, coumarins, alkaloids, flavonoids, tannins, and saponins through qualitative screening. Quantitative analysis demonstrated significant amounts of phenolic compounds (29.435 ± 0.571 mg GAE/g of dry extract), flavonoids (6.711 ± 0.272 mg QE/g of dry extract), and tannins (274.037 ± 11.3 mg CE/g of dry extract). The administration the hydroethanolic extract in two concentrations (1 or 2 g/kg) to male Swiss mice exhibited no marked adverse effects, as evidenced by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activity levels. In addition, the extract significantly reduced skin hyperplasia and inflammation induced by UV/sulfuric acid treatment as noted in tissue analyses and decreased protein expression of nuclear proliferation marker (Ki-67). This improvement was associated with a marked decrease in oxidative stress, as indicated by diminished lipid peroxidation levels, and restoration of the activity of endogenous antioxidant enzyme catalase (CAT) to control levels. Our findings demonstrated the potential of Orbea variegata hydroethanolic extract to be considered as a treatment for skin cancer, exhibiting its apparent safety and efficacy in reducing inflammation and carcinogenesis in a UV/sulfuric acid-induced Swiss mouse model, attributed to its phytochemical content and associated antioxidant activities.

The immune checkpoint VISTA is associated with prognosis in patients with malignant uveal melanoma.

Introduction: Uveal melanoma (UM) is a rare yet deadly tumor. It is known for its high metastatic potential, which makes it one of the most aggressive and lethal cancers. Recently, immune checkpoints such as Programmed cell Death protein-1 (PD1) and Cytotoxic T-Lymphocyte-Associated significantly increasing patient survival in multiple human cancers, especially cutaneous melanoma. However, patients with UMs were excluded from these studies because of their molecular characteristics, which tend to be widely different from those of cutaneous melanoma. This study aimed to analyze the expression of V domain Ig Suppressor T-cell Activation (VISTA), a novel immune checkpoint, to evaluate its prognosis significance and its correlation with PD1 and CTLA-4. Methods: Evaluation of VISTA, CTLA-4, and PD1 expression was performed through TCGA database analysis and immunohistochemistry using two independent cohorts with primary malignant UM. Results and discussion: Our results showed that VISTA expression was associated with tumor aggressiveness, T cell exhaustion, and the shortest median overall survival among patients. Surprisingly, PD1 protein expression was negative in all patients, whereas CTLA-4 expression was high in patients with advanced stages. Our findings suggest that VISTA may be a prognostic marker and an attractive treatment strategy for immunotherapy in patients with UM. Exploring its expression profile may predict response to immunotherapy and may lead to the improvement of precision therapy in malignant uveal melanoma patients.

Metachronous ureteral metastasis of a gastric adenocarcinoma: a case report and review of literature.

BACKGROUND: Ureteral metastasis from gastric cancers are rare and can be a cause of ureteral obstruction. There have been few published case reports in the literature. In this paper, we report an additional case and a review of the literature of all the previous reported cases. CASE PRESENTATION: A 67 years old North African women who was treated four years before for a gastric adenocarcinoma, presented with abdominal pain. Imaging and endoscopy showed a mural stenosis of the left ureter, without any other abnormality. Histopathology confirmed the gastric origin of the metastasis. A palliative chemotherapy was foreseen, but due to the deterioration of the general condition of the patient, she received palliative care. We have also reviewed the literature and reported the previously published cases of ureteral metastasis from gastric cancer. CONCLUSIONS: It is worth recalling that in a context of neoplasia and with the presence of signs of ureteral obstruction, it is important to keep in mind the possibility of a ureteral metastasis.

Atypical Cutaneous Viral Infections Reveal an Inborn Error of Immunity in 8 Patients.

Unusual viral skin infections might be the first clinical manifestation in children with an inborn error of immunity (IEI). We performed a prospective study from 1 October 2017 to 30 September 2021, at the Department of Pediatric Infectious Diseases and Clinical Immunity of Ibn Rochd University Hospital-Casablanca. During this period, on 591 patients newly diagnosed with a probable IEI, eight of them (1.3%), from six independent families, had isolated or syndromic unusual viral skin infections, which were either profuse, chronic or recurrent infections, and resistant to any treatment. The median age of disease onset was nine years old and all patients were born from a first-degree consanguineous marriage. By combining clinical, immunological and genetic investigations, we identified GATA2 deficiency in one patient with recalcitrant profuse verrucous lesions and monocytopenia (1/8) and STK4 deficiency in two families with HPV lesions, either flat or common warts, and lymphopenia (2/8), as previously reported. We also identified COPA deficiency in twin sisters with chronic profuse Molluscum contagiosum lesions, pulmonary diseases and microcytic hypochromic anemia (2/8). Finally, we also found one patient with chronic profuse MC lesions and hyper IgE syndrome, (1/8) and two patients with either recalcitrant profuse verrucous lesions or recurrent post-herpetic erythema multiforme and a combined immunodeficiency (2/8) with no genetic defect identified yet. Raising clinicians awareness that infectious skin diseases might be the consequence of an inborn error of immunity would allow for optimized diagnosis, prevention and treatment of patients and their families.

A Generalized Form of Lichen Planus Pemphigoid Induced by an Oral Antidiabetic.

Lichen planus pemphigoid (LPP) is a rare autoimmune bullous dermatosis, although it is frequently idiopathic, the induced form is rare and there are few inducing drugs. We report a case of LPP induced by a gliclazide. A 68-year-old female patient with type 2 diabetes on gliclazide for three months presented with an eight-week history of generalized erythematous-papular eruption. Then she developed blisters on her forearms with oral mucosa involvement. A diagnosis of gliclazide-induced LPP was made based on a skin biopsy and imputability. The patient was treated with systemic corticosteroid with an improvement. LPP is a rare entity; its diagnosis is a challenge as it represents an overlap between lichen planus and bullous pemphigoid.

Verrucous Melanoma of the Scalp Initially Misdiagnosed as Seborrheic Keratosis.

Verrucous melanoma (VM) is a rare entity that presents diagnostic difficulty on both clinical and histopathologic grounds. Clinically, this tumor can be mistaken for a benign non-melanocytic lesion, particularly seborrheic keratosis (SK), as they both share several similarities, such as the homogenous pigmentation, the verrucous surface, and the roughly well-defined borders. In our patient's case, her verrucous lesion was initially misdiagnosed as SK by a general practitioner two months prior to her admission. Upon physical examination, the lesion was indeed suggestive of SK but a VM was not discarded. Biopsy revealed melanoma. Standard treatment of SK often includes electrodesiccation or cryotherapy, which potentially might worsen and delay the diagnosis of melanoma with subsequent implications for therapeutic management and prognosis. We report this case to increase awareness and knowledge about VM, which may lead to earlier diagnosis and improved outcomes.

Ki-67 proliferation index to further stratify invasive breast cancer molecular subtypes: Northern African comparative cohort-study with external TCGA-BRCA and METABRIC validation.

Introduction: breast cancer (BC) is a malignancy with very high incidence and mortality in Africa, especially in Western Africa, where more than 25 thousand deaths are registered every year. Not all BC have the same prognosis, and being able to personalize treatment and predict aggressiveness is of crucial importance. The purpose of our study is to explore further subdivisions associated with prognosis, beyond breast cancer molecular classification that is routinely established in pathology departments. Methods: we conducted a 5-year retrospective cohort study on 1266 invasive BC of Moroccan patients, collected at the Pathology Department of Ibn-Rochd University Hospital in Casablanca, and followed at King Mohammed VI National Centre for the Treatment of Cancers. We elaborated an Estimation-Maximization Clustering, based on the main BC biomarkers: Ki-67, HER2, estrogen and progesterone receptors, evaluated by immunohistochemistry. Two independent datasets (TCGA-BRCA and Metabric) were also analyzed to assess the external reproducibility of the results. Results: each molecular subgroup could be partitioned into two further subdivisions: Cluster1, with average Ki-67 of 16.26% (±11.9) across all molecular subgroups and higher frequency within luminal BC, and Cluster2, with average Ki-67 of 68.8%(±18) across all molecular subgroups and higher frequency in HER2 as well as in triple-negative BC. Overall survival of the two Clusters was significantly different, with 5-year rates of 52 and 37 months for Custer1 and Cluster2, respectively (p=0.000001). Moreover, mortality rates within the same molecular subgroup, especially in luminal B HER2-, varied remarkably depending on Cluster membership (6% for C1 and 18% for C2 after 1 year of follow-up). Two different algorithms to evaluate the prognostic importance, variable selection using random forests (VSURF) and Minimal depth, ranked the subdivision proposed as one of the 4 most influential features being able to predict patient survival better than several histoprognostic features, both in the Moroccan and in the external datasets. Conclusion: our results highlight a new refinement of the BC molecular classification and provide a simple and improved way to classify tumors that could be applied in low to middle-income countries. This is the first study of its kind addressed in an African context.

Papulonodular Mucinosis Associated With Subacute Lupus.

Papulonodular mucinosis is a rare but well-documented finding associated with systemic and cutaneous forms of lupus erythematosus (LE). It occurs exceptionally in association with subacute cutaneous lupus erythematosus (SCLE). Its etiology and pathogenesis remain to be elucidated. Herein, we report a case of papulonodular mucinosis associated with SCLE in a middle-aged woman. On physical examination, she presented with multiple flesh-coloured asymptomatic papules and nodules on the trunk and upper extremities. A biopsy specimen taken from a nodule showed mucin within the dermis with hypodermis and perivascular lymphocytic inflammation. Considering that the proportion of patients with cutaneous lupus mucinosis who progress to systemic lupus is uncertain, we suggest following these patients closely for evidence of multisystem disease.

The Proliferating and Malignant Proliferating Trichilemmal Cyst: An Anatomo-Clinical Study of Three Cases.

Background: The proliferating and malignant proliferating trichilemmal cysts (MPTC) are rare adnexal tumors. We report 3 cases through which we will detail the anatomo-clinical characteristics of these tumors. Cases: Two patients, 60 and 56 years old, consulted for multiple scalp nodules, one of which had changed with the appearance of a central ulceration. The removal of the remaining scalp nodules was in favor of PTCs. The third patient presented with an ulcerative lesion occupying the vertex. Skin biopsy found trichilemmal-type keratinization associated with areas of necrosis concluding with a MPTC. Discussion: The PTC is a transitional form between the trichilemmal cyst (TC) and the MPTC. The increase in the size of a TC and ulceration are sufficient signals to suspect this evolution.

Autoimmune Bullous Dermatosis Following COVID-19 Vaccination: A Series of Five Cases.

Autoimmune bullous diseases (AIBDs) are a heterogeneous group of diseases characterized by cutaneous and mucosal vesicles, blisters, and erosions. Several factors can trigger this disease, including vaccines; but this entity remains very rare. We hypothesized that vaccination against coronavirus disease 2019 (COVID-19) could trigger an immunological response in genetically predisposed individuals. We report five cases of new-onset autoimmune bullous diseases triggered by the COVID-19 vaccine. Clinical and histopathological examinations confirmed the diagnosis of bullous pemphigoid (BP) in three patients and pemphigus in the other two. According to the French method of imputability, the pharmacovigilance investigation showed an I5B4 causality assessment score for the vaccines, interpreted as highly probable, for all the patients. The diagnosis of vaccine-induced autoimmune bullous dermatosis was highly suspected. One patient's condition improved by dermocorticoids alone, while the other four required oral corticosteroid therapy at 0.5 mg/kg/day, which led to a favorable outcome.

Subungual Exostosis: A Case Series of 48 Patients.

BACKGROUND: Subungual exostosis is an unusual benign nail tumor, mostly located on the big toe. It generally affects young people and manifests as uncomfort during footwear. METHOD: A monocentric retrospective study was conducted at the outpatient consultation for nail disorders at the Department of Dermatology of the University of Casablanca, Casablanca, Morocco, between April 2006 and October 2019. RESULTS: We diagnosed subungual exostosis in 48 patients, including 25 men and 23 women, with an average age of 20 years. The subungual exostosis was located on the hallux in 34 cases, the second toe in 10 cases, and the index finger in 2 cases. Nail trauma was found in 27 patients. The tumor was entirely excised in all the patients. CONCLUSION: Large series of subungual exostosis are reported by orthopedic surgeons. However, our outpatient consultation for nail disorders allowed the diagnosis and appropriate management of subungual exostosis.

First Subungual Cryptococcosis Described in an HIV Patient with Disseminated Cryptococcosis.

BACKGROUND: Cutaneous cryptococcosis occurs in 10-15% of patients with disseminated cryptococcosis. It typically presents as papulonodular molluscum-like lesions, but it can also produce a wide variety of lesions. Cryptococcal infection of the nail unit has never been reported. CASE REPORT: A 28-year-old woman with a history of HIV with disseminated cryptococcosis in complete remission was referred to evaluate a subungual swelling of the right middle finger. Examination revealed an ulcero-burgeoning nodule over the right middle finger's subungual area with onycholysis, eschar, and erosion. An excisional biopsy was performed. Histopathological analysis demonstrated multiple histiocytic granulomas centered by encapsulated yeast cells. Culture grew Cryptococcus neoformans var. neoformans. After 9 months of follow-up, there was no recurrence of the lesion. DISCUSSION: It is the first reported case of nail involvement in the course of cutaneous cryptococcosis. Definitive diagnosis required pathology and culture. Cryptococcal infection of the nail unit was recalcitrant to systemic therapy while the remaining infection cleared. Our case report suggests that surgical excision associated with systemic therapy is the best treatment approach for subungual cryptococcosis. Recognition of rare manifestations of cutaneous cryptococcosis, such as ours, is essential because HIV cases increase continuously.

[Cutaneous complications following hematopoietic stem cell transplantation]. / Complications cutanées post-allogreffe de cellules souches hématopoïétiques.

BACKGROUND: Hematopoietic stem cell allograft is a treatment for patients with severe constitutional or acquired hematopoietic system diseases. This act is always linked to complications requiring multidisciplinary care. Our study describes the post-allograft cutaneous complications. METHODS: A prospective study was conducted at the Hematology department of "20 Août Hospital" in Casablanca during a period going from January 2018 to December 2020; including all patients who presented acute or chronic cutaneous complications post-allograft. RESULTS: Twenty-five patients were included. All patients received induction chemotherapy (Busulfan/Fludarabine or Busulfan/Melphalan). A skin infection was found in 8 patients : four cases of Malassezia folliculitis, one case of perineal zona, one case of genital herpes, one case of varicella and one case of Candida sepsis. The acute graft versus host reaction was found in 3 patients, revealed by an erythematous rash all over the body. The chronic graft versus host reaction was found in five patients on a lichenoid form. Nine patients had a hyperpigmentation of the folds followed by detachment in the same areas, concluding to a Busulfan toxidermy. DISCUSSION: Hematopoietic stem cell allograft has many complications. The literature mainly specifies hematological and digestive complications, while skin complications are little described. Our series is special by reporting different types and mechanisms of skin complications that can occur; with a predominance of skin graft-on-host reactions and infections. It also reports an unusual Busulfan toxidermy.

Spontaneous regression of angiolymphoid hyperplasia with eosinophilia (AHLE): A case report.

INTRODUCTION: and importance - Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare benign microvascular proliferation. It is clinically characterized by intradermal or subcutaneous papules and/or nodules. Treatment consists mainly of surgery or laser therapy, with a high recurrence rate. Spontaneous regression is rare but possible. CASE PRESENTATION: A 72-year-old man presented for an erythematous plaque on his scalp. Physical examination demonstrated a large angiomatous indurated subcutaneous plaque. The lesion was not pulsatile. The doppler ultrasound revealed no underlying vascular malformation. The biopsy revealed an ALHE. No further treatment was carried out. During the follow-up, the lesion gradually subsided. After one-year follow-up, the lesion had regressed with no sign of recurrence. CLINICAL DISCUSSION: There are different treatment modalities for AHLE management, including surgical excision, cryotherapy and lasers. However, none of these modalities has provided consistent results and recurrence after treatment is common.). Rare instances of spontaneous regression have been reported. CONCLUSION: Given the rarity of cases of spontaneous resolution, ALHE may be considered as a chronic condition, especially since recurrences are frequent. A "wait and see" approach can be proposed in some specific situations.

Nail Mycosis Fungoides: A New Case.

Ungueotropic mycosis is a rare form of mycosis fungoides. We present the case of a 32-year-old female patient with advanced tumor stage mycosis fungoides, presenting a phanerial involvement with lymphoid infiltration of the nails and scalp confirmed by histology and immunohistochemistry.