AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

A rare case of primary cutaneous follicle centre lymphoma presenting as a giant tumour of the scalp and combined with JAK2V617F positive essential thrombocythaemia.

Primary cutaneous follicle centre lymphoma (PCFCL) is a rare cutaneous B cell lymphoma in middle-age adults with excellent prognosis. Here we present a case of a patient with a PCFCL in the form of a giant tumour of the scalp in combination with a myeloproliferative neoplasm, JAK2V617F positive essential thrombocythaemia. This case may be of interest because of the favourable outcome in spite of the large size of the PCFCL, the rare combination with essential thrombocythaemia and because it contributes to discussion on the role of JAK2 mutation in such patients.

[Erythema scarlatiniforme desquamtivum recidivans or Féréol-Besnier disease: an uncommon condition]. / Erythème scarlatiniforme desquamatif récidivant ou maladie de Féréol-Besnier: une entité peu connue.

The erythema scarlatiniforme desquamtivum recidivans (ESDR) is rare condition, characterized by an erythema followed by large lamellar scaling. Two variants are described, a generalized and localized one. The generalized variant initially presents with fever, flue-like symptoms followed by a widespread macular erythema rapidly evolving into large lamellar scaling, except for the head where scaling is finer. The localized form is often asymptomatic and the large lamellar scaling is limited to the palms and soles. ESDR can recur within weeks or years after the first outbreak, with the localized form being more frequent at recurrence. The aetiology remains unknown. Most authors agree on a hyperergic reaction to drugs, viral and bacterial infections. Differential diagnosis includes several conditions. The medical history and the striking presentation help in making the diagnosis.

[Heparins and skin reactions: from diagnostic to management]. / Héparines et réactions cutanées: du diagnostic a la prise en charge.

The use of heparins in the prophylaxis and treatment of thromboembolic diseases shows non-negligible risks of cutaneous lesions, which are very frequently underestimated by physicians. As this risk often originates from either delayed-type hypersensitivity reactions or life-threatening heparin-induced thrombocytopenia, a quick diagnosis and an adapted management are thus crucial. Furthermore, as most cases are emergencies, allergologic testing cannot be considered in the first place. In this context, an overview of the therapeutic as well as management recommendations is presented, taking into account the most recent treatments.

Response of mucocutaneous lesions to rituximab in a case of melanoma differentiation antigen 5-related dermatomyositis.

We report the first case in Western Europe of a person presenting with dermatomyositis associated with melanoma differentiation antigen 5 antibodies. She sequentially developed severe mucocutaneous erythematous and itchy lesions of the face, scalp, neck, knees and recurrent aphthae. In addition she presented painful, periungual, edematous digital lesions and small ulcers with digital necrosis. Her rapidly evolving, near-fatal interstitial lung disease responded to high-dose intravenous cyclophosphamide. However, her recurrent mucocutaneous manifestations improved only after rituximab administration.

Deep dissecting hematoma: an emerging severe complication of dermatoporosis.

OBJECTIVE: To outline the characteristics of deep dissecting hematoma (DDH). DESIGN: Retrospective medical record review. SETTING: Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland. PATIENTS: Thirty-four patients with DDH. INTERVENTIONS: Deep incision or surgical debridement was performed in all the patients. Direct closure of the incision was possible in 6 patients, and split-thickness skin grafting was applied to 17 patients. MAIN OUTCOME MEASURES: Sex of the patient, the affected area, presence of dermatoporosis, presence of systemic treatment, initial and late symptoms, anatomic location of DDH, and the mean length of hospital stay. RESULTS: Most frequently, elderly women were affected (mean age, 81.7 years); women outnumbered men by a ratio of 5:1. In all the patients, the leg was the affected part of the body. All the patients, except for the 2 youngest ones, had advanced dermatoporosis, and the most severe form was seen in the older patients who were receiving long-term treatment with systemic corticosteroids. Half of the patients were receiving anticoagulation drugs. The initial symptoms in all the patients were pain and swelling of the leg. Erythema and edema without fever were observed. Skin necrosis developed as a late manifestation. Erysipelas was the initial diagnosis in up to 14 patients who had been treated with antibiotics before admission. The mean delay before hospital referral was 16.4 days. Magnetic resonance imaging and histopathological analysis confirmed deep anatomical location of DDH. Hospital treatment consisted mainly of deep incision and debridement followed by direct closure, skin grafting, or wound healing per secundam. The mean length of hospital stay was 3.5 weeks. CONCLUSIONS: Deep dissecting hematoma is an emerging clinical entity and a major complication of dermatoporosis. Prompt diagnosis and treatment is a major factor for the prognosis. Health care professionals, especially general practitioners, should be aware of the symptoms and signs of this condition as well as the risk factors involved. Given the high cost of treatment, in addition to the inconvenience it causes for the patient, preventive measures should be implemented early.

Intravenous immunoglobulin: properties, mode of action and practical use in dermatology.

Since they were first administered to patients with antibody deficiency disorders over 50 years ago, human intravenous immunoglobulin preparations have been used successfully to treat a rapidly increasing number of autoimmune and inflammatory disorders, among which are a series of cutaneous autoimmune and inflammatory diseases. These include dermatomyositis, Kawasaki's disease, a number of autoimmune bullous diseases, severe adverse drug reactions, and other autoimmune and/or allergic conditions, such as atopic dermatitis. Although only a minority of these indications (dermatomyositis, Kawasaki's disease) are officially registered or based on double-blind, placebo-controlled clinical studies, the observed efficacy and safety profile of currently available intravenous immunoglobulin sometimes makes this a treatment of choice for initiation of therapy or for replacement of more toxic alternatives, such as systemic immunosuppressive medications. The increasing use of intravenous immunoglobulin has been associated with further understanding of its mechanism(s) of action, clinical manipulation and associated side-effects, as well as the introduction of improved or new types of intravenous immunoglobulin. This paper reviews the current knowledge of the mode of action of intravenous immunoglobulin, its reported therapeutic effects in cutaneous disease, its mode of administration and safety profile, and compares the currently available intravenous immunoglobulin preparations.

An illustrative case of Muir-Torre syndrome: contribution of immunohistochemical analysis in identifying indicator sebaceous lesions.

BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the association of at least 1 cutaneous sebaceous tumor and 1 internal malignancy, often arising in the gastrointestinal tract. It is secondary to germline mutations in DNA mismatch repair genes, mainly MLH-1 and MSH-2. OBSERVATIONS: We report the case of a 54-year-old man with a 2-year history of skin-colored papules clinically reminiscent of large sebaceous hyperplasias on the nose and back, but histologically diagnosed as sebaceous adenomas and epitheliomas. His family history was positive for colon cancer in the mother and 2 brothers. A colonoscopy done during the hospitalization revealed 2 sessile polyps in the left colon, both showing a low-grade dysplasia on the biopsy specimen. Immunohistochemical staining performed on the cutaneous and colic biopsy specimens revealed a lack of expression of MSH-2 and MSH-6. Genetic testing revealed microsatellite instability in the colon and cutaneous tumors. CONCLUSION: The immunohistochemical testing for MSH-2, MSH-6, and MLH-1 is useful for rapid identification of an underlying mismatch repair defect and early diagnosis of MTS.

Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: report of 4 cases and review of the literature.

BACKGROUND: High-dose intravenous immunoglobulins (IVIGs) are increasingly used to treat inflammatory and/or autoimmune disorders. In dermatology, they provide therapeutic benefit in Kawasaki disease and certain cases of dermatomyositis. While most adverse effects following IVIG treatment are not severe, occasionally more severe adverse effects occur, including anaphylactic reactions and acute, usually transient, renal failure. OBSERVATIONS: We report 4 cases of a characteristic severe extensive eczematous reaction that occurred approximately 10 days after IVIG infusion for polyradiculoneuritis. In all cases, onset was characterized by dyshidrotic lesions on the palms, rapidly followed by pruriginous maculopapular lesions involving the whole body. All patients were treated with topical and/or systemic steroids, and complete resolution of skin lesions was observed within 1 month. To date, 33 cases of cutaneous rash following IVIG infusion have been reported in the literature, mostly in neurology journals, and the features are identical to those reported herein. CONCLUSIONS: Severe eczematous skin reaction with a characteristic initial localization to the palms and/or soles that then extends to the rest of the body is a rare but characteristic adverse effect of high-dose IVIG therapy. Although the precise mechanism of this cutaneous eruption remains to be elucidated, its occurrence within days of IVIG infusion, its characteristic distribution at onset, and its clinical course should be recognized by dermatologists.

Telemedical wound care using a new generation of mobile telephones: a feasibility study.

BACKGROUND: Leg ulcers are an important cost factor in health care systems. It has been shown that a telemedical wound care consultation can improve quality of care and help reduce costs. In this study, we evaluated the feasibility of telemedical wound care using a new generation of mobile telephones with integrated cameras. OBSERVATIONS: Three physicians separately evaluated 61 leg ulcers for the following 9 variables: epithelialization, fibrin, necrosis, and granulation tissue at the center and normal border, erythema, cyanosis, eczema, and hyperpigmentation at the periphery. One physician performed the face-to-face consultation (gold standard), and 2 others performed the remote evaluation. The image was obtained with the mobile telephone and immediately sent via e-mail. To measure the agreement of the evaluation among the 3 physicians, we used Cohen kappa statistics. Overall, the agreement between the remote and face-to-face evaluations was very good, with kappa values of up to 0.94 The image quality was judged to be good in 36 cases (59%) and very good in 12 (20%). The participants felt comfortable making a diagnosis based on the pictures in 50 cases (82%). CONCLUSION: Although this study was performed with the first generation of these devices, we were able to demonstrate the feasibility of such a telemedical wound care consultation.

Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study.

BACKGROUND: Stevens-Johnson syndrome (SJS) is a severe cutaneous drug reaction associated with considerable morbidity, possible transition to toxic epidermal necrolysis (TEN) and death in certain cases. OBJECTIVE: To determine whether treatment with high-dose IVIG in SJS patients may improve outcome. METHODS: Data from 12 patients (collected between January 1997 and November 2000 from 7 university dermatology centers in Europe and North America) diagnosed with SJS according to a recent consensus definition was analyzed retrospectively. All patients had progressive ongoing epidermal detachment at the time of treatment initiation. Patients with overlap syndromes and TEN were excluded. Tolerance, survival at 45 days after onset and total healing time were assessed. RESULTS: Twelve SJS patients (mean age 44 years) were treated with IVIG at a mean dose of 0.6g/kg/day for an average of 4 days. An objective response to IVIG infusion was observed in all patients within a mean of 2 days, and the overall survival rate was 100%. Total skin healing occurred, on average, within 8.3 days. Time to total healing was shorter in a group of patients with fewer severe underlying diseases who had received IVIG infusion rapidly after the onset of skin lesions. CONCLUSION: High-dose IVIG may be effective in blocking the progression of SJS and reducing the time to complete skin healing.

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases.

OBJECTIVE: To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis (TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fas-mediated cell death. DESIGN: Multicenter retrospective analysis of 48 consecutive TEN patients treated with IVIG. SETTING: Fourteen university hospital dermatology centers in Europe and the United States. PATIENTS: Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]). INTERVENTIONS: Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG batches to inhibit Fas-mediated cell death. MAIN OUTCOME MEASURES: Objective response to IVIG treatment, final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. RESULTS: Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days]) was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43 patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro. CONCLUSIONS: Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3 consecutive days (1 g/kg per day for 3 days).