Exploring the role of vitamin D-VDR pathway in pemphigus foliaceous: a novel perspective on disease pathogenesis.

Several auto-immune diseases have been linked to vitamin D deficiency as a contributing environmental factor. Its pleiotropic effects on the immune system, especially its essential role in maintaining immune tolerance, make the vitamin D pathway of great interest. In this study, we focused on Pemphigus foliaceous (PF) in Tunisian population. we aimed to quantify the Serum 25[OH]D levels using chemiluminescence assay and to analyze the differential expression of the VDR, CYP27B1 and CYP24A1 genes in the circulating blood cells and lesional skin tissue of PF patients using Q-PCR. A genetic explanation was then sought to explore any direct relationship between tag polymorphisms and the inherited features of PF. Results confirmed a vitamin D hypovitaminosis in Tunisian PF patients. Interestingly, a differential gene expression correlated to the disease stratification was noted. Indeed, at the systemic level, an upregulation of VDR and CYP27B1 genes was observed in healthy controls compared to PF patients. Notably, in lesional skin tissue, the clinical and serological remission phase was correlated with high transcriptional levels of the VDR gene and conversely a drop in expression of the CYP24A1 gene. Genetic analysis indicated the involvement of the most appealing polymorphisms, rs2228570 and poly (A) microsatellite, in PF etiopathogenesis. Indeed, CAC13 haplotype was associated with a higher risk of PF development. Our findings suggest that alterations in the vitamin D-VDR pathway may influence PF physiopathology, making this pathway a potential target for pharmacological modulation, especially for cortico-resistant PF patients.

Unraveling the role of the vitamin D-VDR pathway in pemphigus vulgaris from Tunisian patients.

Vitamin D dysregulation has been recognized as a factor that may cause or aggravate autoimmunity. Vitamin D deficiency was found to be common in pemphigus vulgaris (PV) in different populations. This study aimed to investigate the vitamin D-VDR pathway in PV in the Tunisian population. A serological study was carried out to determine the vitamin D status in newly diagnosed PV patients. CYP27B1, CYP24A1 and VDR mRNA expression was assessed using quantitative real-time PCR in peripheral blood mononuclear cells (PBMC) from untreated newly diagnosed and treated PV patients. In addition, a genetic study was accomplished on VDR polymorphisms to investigate the changes in VDR gene expression. Overall, the serological study confirmed the hypovitaminosis D in newly diagnosed PV patients. Vitamin D-VDR pathway gene expression showed downregulation of CYP27B1 and CYP24A1 mRNA in first-discovery patients compared to healthy controls, while VDR mRNA was highly expressed in newly diagnosed PV patients. Moreover, CYP27B1, CYP24A1 and VDR mRNA were significantly upregulated in chronic disease severity groups compared to mild disease groups. The genetic study showed low VDR gene expression in carriers of FokI > CC genotype, which was more frequent among PV patients, and FokI > C-TaqI > C-ApaI > A-polyA > A16 haplotype, suggesting that the VDR gene polymorphisms testing can provide useful information for PV treatment decision-making. In conclusion, our findings underline the impact of vitamin D-VDR pathway disruption in the PV pathophysiology in Tunisian patients.

Congenital liquified subcutaneous fat necrosis in a newborn: an unusual case.

Subcutaneous fat necrosis of the newborn is a self-limited disorder of the panniculus that arises in the first six weeks of life. Some differential diagnoses may be difficult such as bacterial cellulitis or erysipelas. The prognosis is usually favorable but there are serious complications for which the patient must be regularly monitored, especially hypercalcemia. We report a case of a full-term newborn with a liquidated area of subcutaneous fat necrosis. A surgical incision was performed because of the discomfort and the lack of regression. Hypercalcemia and nephrocalcinosis appeared afterward. A set of clinical, biological, and histological arguments allows the diagnosis of subcutaneous fat necrosis. Follow-up to early detection and to manage such complications is necessary.

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

International Consensus Definition and Diagnostic Criteria for Generalized Pustular Psoriasis From the International Psoriasis Council.

Importance: Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons. Objective: To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method. Evidence Review: The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion. Findings: In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques." Conclusions and Relevance: The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

Direct medical cost related to the management of pemphigus: A pilot Tunisian study.

INTRODUCTION: Pemphigus is a therapeutically challenging disease with high morbidity and economic burden. First-line prescription of rituximab remains limited in Tunisia due to its high cost. Systemic steroids remain the standard of care but are associated with a major risk of morbidities and higher treatment costs. AIM: To assess the direct medical costs of pemphigus in Tunisia. METHODS: Retrospective estimation of direct medical costs during the 18 months following the diagnosis using the "bottom-up approach" in the Dermatology Department of Hedi Chaker Hospital, Sfax, Tunisia. RESULTS: Total medical costs were estimated at 38745.7 €, with an average cost of 1 210 € per patient and per year: paraclinical investigations (46%), medical treatment (30%), hospitalization (21%) and outpatient visits (3%). The average cost was the highest in the age group of 15-24 years (1553 €). Treatment costs related to corticosteroid-induced morbidity were estimated at 1208 €. CONCLUSIONS: The management of pemphigus in Tunisia needs to be adapted to take into account the health economic analysis in order to reduce overall disease costs and the burden of steroid-induced morbidities.

Characteristics of DRESS Syndrome in the Elderly: A Comparative Study of 55 Patients.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare drug reaction characterized by a skin rash, eosinophilia, and organ involvement. Objective: Our purpose is to focus on the clinical and epidemiological characteristics of DRESS in the elderly and to identify the incriminated drugs. Methods: This is a retrospective study including patients, hospitalized for DRESS with a RegiSCAR ≥4. The population was divided into 2 groups according to age: 65 years or older (G1) and <65 years (G2). The statistical study was performed using the comparative and multivariate analysis. Results: We included 55 patients (30.9% G1 and 69.1% G2). Skin manifestations were comparable in both groups. Lymphadenopathy was less common in G1 with a statistically significant difference (P = 0.012). Renal impairment was more frequent in the elderly with a statistically significant result (P = 0.005). DRESS in the elderly group was significantly associated with the occurrence of sepsis (P = 0.008). Allopurinol was the most common culprit associated with DRESS in G1 (P = 0.001). Relapses and recurrences were comparable in both groups (P = 0.71). Conclusions: DRESS in the elderly is associated with a high risk of complications, mainly kidney involvement and sepsis. Allopurinol is the most incriminated drug.

Follicular Basaloid Hamartoma and Associated Cutaneous Tumors: Clinical, Histopathological and Dermoscopic Aspects.

Background: Basaloid follicular hamartoma is an uncommun benign neoplasm of the hair follicule. The linear form of basaloid follicular hamartoma can be associated with basal cell carcinoma.OBJECTIVE: We report a case of a patient with multiple basal cell carcinomas developing on a congenital lesion allowing the diagnosis of basaloid follicular hamartoma on histopathology. Methods: Each lesion was evaluated by two dermatologists. All biopsy specimens were routinely stained with hematoxylin-eosin. Results: A 76 year-old-man consulted our dermatology departement for erythematous papules spread over the left lower limb. The lesion had been evolving since birth with flesh-colored to pinkish papules following Blaschko's lines from the root of the thigh to the foot. Three months before consultation, the papules increased in size leading to nodules with sometimes an ulcerated center. Dermoscopy under polarized mode displayed for ulcerated lesions (A) yellow-brownish crusts and ulceration surrounded by blue-grey ovoid nests, subtle short white streaks, brown dots and linear/arborising vessels. For nodular lesions (B), dermoscopic features are white pinkish hue, dotted and linear vessels, brown dots, blue-grey structureless areas and white prominent shiny streaks. There were some more erythematous inflamed and eroded areas in the background with a reversed honeycomb white network on dermoscopy (C), polymorphous vessels, whitish scales, ulcerations and milia-like cysts. The background lesion showed varied dermoscopic structures on a flesh colored slightly pinkish bottom (D). Histolopathology concluded for lesions A to an infiltrating and nodular basal cell carcinoma, (B) and (C) to fibroepithelioma of Pinkus and (D) to basaloid follicular hamartoma. Conclusion: Several case reports have documented dermoscopic features of a solitary basaloid follicular hamartoma. However, further studies are required to specify any reproducible features.

Bullous Pemphigoid Associated With Dipeptidyl Peptidase-4 Inhibitors: A Case Report and Review of Current Evidence.

Dipeptidyl peptidase-4 inhibitors (DPP-4i), or gliptins, are a widely used glucose-lowering agents. A growing amount of evidence pointed to a possible role of DPP-4i in the induction of bullous pemphigoid (BP), which is an auto-immune skin blistering disease that mainly affects the elderly. In this article we discuss a case of DPP-4i associated BP and we provide an updated review of the current knowledge regarding this emerging entity. Use of DPP-4i, particularly vildagliptin, was found to significantly increase the risk of BP. BP180 would be in the center of the aberrant immune response. DPP-4i induced BP is thought to be associated with male gender, mucosal involvement, and milder inflammatory phenotype especially in Asian population. Generally, patients may not remit fully after DPP-4i withdrawal only and require either topical or systemic glucocorticoid courses.

Inverted Follicular Keratosis: A Retrospective Study Over 10 Years.

Inverted follicular keratosis (IFK) is a rare benign tumour of the follicular infundibulum characterized by exo-endophytic growing. Generally, the diagnosis of IFK is histopathologically made because clinical differentiation from other lesions is difficult. We present a retrospective series with thirteen patients with histologically confirmed IFK to evaluate the epidemiological, clinical and histopathologic characteristics of IFK. The mean age of the patients at the time of the excision was 53 years with extremes ranging from 19 to 82 years. The sex ratio M/F was 3.3. The lesions affected the face in nine patients mainly the moustache, followed by the scalp in three cases and the arm in one case, and 92% of the localizations are sun-exposed. The diagnosis was never clinically evoked. The lesion had a pink colour in ten cases and was pigmented in two cases and hypopigmented in one case. More than half of the lesions (53%) had a keratotic centre. Histopathological examination showed endophytic intradermal proliferation of basaloid cells with a variable degree of squamoid differentiation. Horn cysts were present in all cases. According to our series, the IFK occurs predominantly in young men, in the face and more specifically in the moustache. Dermoscopy may suggest the diagnosis of the IFK. In fact, a histopathological examination is the gold standard for the diagnosis of the IFK and helps differentiate these benign tumours from possible malignant neoplasms.

An unusual pigmented skin lesion on the nipple-areola area.

Considering the rarity and underdiagnoses of this disorder, a pigmented and hyperkeratotic skin lesion located on the trunk, resembling to acanthosis nigricans should always be investigated for terra firma-forme dermatosis (TFFD) and thus alcohol must be applied. TFFD should be known among dermatologists and can be easily diagnosed and treated with isopropyl alcohol.

miRNA implication in the pathogenesis and the outcome of Tunisian endemic pemphigus foliaceus.

Pemphigus foliaceus (PF) is a bullous autoimmune skin disease diagnosed through sera and skin analyses. PF severity is associated with maintained anti-Dsg1 sera levels and its prognosis is unpredictable. MicroRNA (miRNA), dynamic regulators of immune function, have been identified as potential biomarkers for some autoimmune diseases. This study aimed to assess the miRNA expression of miR-17-5p, miR-21-5p, miR-146a-5p, miR-155-5p and miR-338-3p using quantitative real-time PCR in peripheral blood mononuclear cells (PBMC) and lesional skin samples from untreated and treated PF patients (both remittent and chronic) over 3 months. Overall, miRNA expression was significantly higher in PBMC than in biopsy samples. Blood miR-21 expression was increased in untreated patients compared to controls and had a diagnostic value with an AUC of 0.78. After 6 weeks, it decreased significantly, similar to anti-Dsg1 antibodies and the PDAI score. In addition, a positive correlation was observed between cutaneous miR-21 expression and the disease activity score. Conversely, cutaneous expressions of miR-17, miR-146a and miR-155 were significantly higher in treated chronic patients compared to remittent ones. The cutaneous level of miR-155 positively correlated with pemphigus activity, making it a potential predictive marker for patients' clinical stratification with an AUC of 0.86.These findings suggest that blood miR-21 and cutaneous miR-155 can be used as supplemental markers for PF diagnosis and activity, respectively in addition to classical parameters.

Unusual malar rash with ulceration: What can we expect?

Considering the clinical polymorphism of the disease, longstanding skin lesions located on the face, resembling erysipelas in an endemic area should always be investigated for CL and thus, atypical presentations should be kept in mind.

Trichofolliculoma: A Case Series.

Trichofolliculoma (TF) is a rare benign adnexal follicular tumor, described as hamartoma with follicular differentiation according to some authors. It typically appears during adulthood on the face or scalp as an isolated nodule with protrusion of central tufted hairs. We present a retrospective series of eleven patients with histologically confirmed TF to evaluate epidemiological, clinical, and histopathologic characteristics. The mean age at excision was 46 years with extremes ranging from 20 to 75 years. The sex ratio M/F was 0.37. Clinical presentation was a papule or nodule with an average diameter of 6,7mm (2-15 mm), firm with central pit in 54 percent and visible emerging vellus hairs in 18 percent of cases only. The localization was on the face in seven cases (63.6%) and only four cases were located outside the face (scalp [n=2], sub mammary fold [n=1] and shoulder [n=1]). Histologically, a cystically dilated hair follicle containing keratinous material with several mature and immature branched follicular structures is described in all cases. According to our series, TF occurs predominantly in women without age predilection, in the face. Central tufted hairs are only found in a minority of cases corresponding histologically to many secondary vellus hair follicles. In fact, histopathological examination is the gold standard for the diagnosis because clinical diagnosis could be challenging. Histology and dermoscopy may vary according to the age of the lesion. To date, only few case series have been published.

Whitish patches on the buccal mucosa: Role of dermoscopy.

Morsicatio is caused by chronic self-inflicted biting of the buccal mucosa that results in clinically whitish plaques. It is frequently confused with other dermatological mucosal disorders. To avoid needless invasive procedures, dermoscopy can help with differential diagnosis. Dermoscopy shows whitish and yellowish structureless areas and lines, small erosions, and some white scales. The lack of additional, more specific signs such as Wickham striae is crucial to guide the diagnosis.

Clinical Characteristics and Outcomes of Generalized Pustular Psoriasis Flares.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, neutrophilic skin disease that can become life-threatening if flares are untreated. There are limited data describing the characteristics and clinical course of GPP disease flares with current treatment options. OBJECTIVE: The aim of the study was to describe the characteristics and outcomes of GPP flares using historical medical information from patients enrolled in the Effisayil™ 1 trial. METHODS: Investigators collected retrospective medical data characterizing patients' GPP flares prior to clinical trial enrollment. Data on overall historical flares were collected, as well as information on patients' typical, most severe, and longest past flares. This included data on systemic symptoms, flare duration, treatment, hospitalization, and time to clearance of skin lesions. RESULTS: In this cohort (N = 53), patients with GPP experienced a mean of 3.4 flares per year. Flares were painful, associated with systemic symptoms, and often triggered by stress, infections, or treatment withdrawal. Resolution of flares was longer than 3 weeks in 57.1%, 71.0%, and 85.7% of documented (or identified) typical, most severe, and longest flares, respectively. GPP flares led to patient hospitalization in 35.1%, 74.2%, and 64.3% of patients for their typical, most severe, and longest flares, respectively. For the majority of patients, pustules took up to 2 weeks to clear for a typical flare and 3-8 weeks to clear for the most severe and longest flares. CONCLUSION: Our findings highlight that current treatment options are slow to control GPP flares and provide context for assessing the efficacy of new therapeutic strategies in patients with a GPP flare.

Late onset of flesh-colored papules of the neck.

Papular elastorrhexis is a rare, acquired disorder of elastic tissue, occurring in adolescent females, characterized by flesh-colored monomorphous papules usually located on the trunk and the proximal portion of the extremities. We report a case in an old woman with atypically isolated localization on the neck.