S. Geller

Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting

The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.

Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene.

Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.

The expanding spectrum of IgA pemphigus: a case report and review of the literature

IgA pemphigus (IGAP) is a rare, distinct variant of pemphigus, currently classified, depending upon the histological features, immunofluorescence staining pattern and autoantibody profile, into two types: subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis. In a patient with a widespread blistering disease of the skin resembling SPD‐type IGAP, we demonstrate the coexistence of IgA reactivity to both epidermal (desmocollins 2 and 3) and basement membrane‐associated (BP180) proteins, suggesting the coexistence of atypical IGAP and linear IgA bullous dermatosis, respectively. This case, together with 20 previous reports of atypical IGAP, underscores the limitations of current classification schemes. Therefore, we suggest reclassifying these cases under the general term ‘IGAP spectrum’.

Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases

Background: Serologic diagnosis of autoimmune blistering disease (AIBD) usually follows a sophisticated multistep algorithm. Objective: We sought validation of a multivariant enzyme‐linked immunosorbent assay (ELISA) in the routine diagnosis of AIBD. Methods: The multivariant ELISA comprising 6 recombinant immunodominant forms of major AIBD target antigens, ie, desmoglein 1, desmoglein 3, envoplakin, BP180, BP230, and type VII collagen was applied in: (1) a cohort of well‐characterized AIBD (n = 173) and control sera (n = 130), (2) a prospective multicenter study with 204 sera from patients with newly diagnosed AIBD with positive direct immunofluorescence microscopy, and (3) a prospective monocenter study with 292 consecutive sera from patients with clinical suspicion of AIBD in comparison with the conventional multistep diagnostic algorithm. Results: Concordant results in the multivariant ELISA compared with direct immunofluorescence microscopy were seen in 94% of patients with pemphigus and 71% of patients with pemphigoid (Cohen &kgr; value, 0.95 and 0.66) and with the conventional multistep diagnostic approach in 91% of patients with pemphigus and 88% of patients with bullous pemphigoid and 93% of autoantibody‐negative sera (Cohen &kgr;, 0.95, 0.84, and 0.78). Limitations: IgA autoantibodies and less common target antigens were not analyzed. Conclusions: The multivariant ELISA is a practical, highly standardized, and widely available novel diagnostic tool for the routine diagnosis of AIBD.

Failure of initial disease control in bullous pemphigoid: a retrospective study of hospitalized patients in a single tertiary center

Bullous pemphigoid (BP) is the most prevalent autoimmune blistering skin disease in Western countries and in Israel. Initial disease control is achieved in 60–90% of BP patients within 1–4 weeks of corticosteroid therapy. In the remainder of patients, recalcitrant disease is controlled with additional immunosuppressive treatment.

A refractory, cutaneous, subepidermal bullous disease

S. Geller, A. Gat, T. Zeeli, E. Schmidt, N. Ishii, T. Hashimoto, D. Zillikens and E. Sprecher Departments of Dermatology and Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Dermatology, University of Luebeck, Luebeck, Germany; and Department of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, Fukuoka, Japan

A novel homozygous deletion in EXPH5 causes a skin fragility phenotype

Epidermolysis bullosa simplex (EBS) is the most common form of EB. Eight different genes have been implicated in the pathogenesis of different types of EBS, but a substantial portion of the cases cannot be attributed to mutations in known genes. Recently, recessive mutations in the gene EXPH5 (encoding exophilin‐5, also known as Slac2‐b) were identified in patients affected with a mild form of EBS. We used immunohistochemistry, Sanger sequencing and PCR–restriction fragment length polymorphism analysis to identify the cause of mild congenital skin fragility in a 3‐year‐old girl. No mutations were detected in KRT5 or KRT14, but we identified a novel homozygous deletion in EXPH5, which was found to cosegregate with the disease phenotype in the family. Our results further expand the spectrum of mutations in EXPH5. Appraisal of the present case against previously reported patients indicate that EXPH5 mutations result in a distinctive skin fragility phenotype, with minimal blistering compared with other forms of basal EBS.

Grover disease and bullous pemphigoid: a clinicopathological study of six cases

Grover disease (GD) is an idiopathic dermatosis that typically manifests as itchy papules over the trunk in middle‐aged men. Bullous pemphigoid (BP) is an autoimmune bullous disease that affects older people. Not only are the two diseases easily distinguishable on clinical grounds, they are also characterized by differences in histopathology, pathogenesis and response to treatment Thus, the co‐occurrence of these two conditions in the same patient is usually considered coincidental. In this report, we present a multicentre retrospective analysis of six patients who developed both GD and BP over a short period of time, and in all cases but one, GD preceded BP. We discuss the clinical and histopathological features of these patients, and the suggested mechanisms of the diseases. We conclude that GD might predispose to the development of BP.

Pemphigoid: diversity in evolution

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