Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans.

BACKGROUND: Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified. OBJECTIVES: We aimed to identify the genetic cause of HLP. METHODS: For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA -extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed -paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated. RESULTS: In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46-62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients. CONCLUSIONS: Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.

Linear IgA bullous dermatosis of childhood.

A 4-year-old boy presented with blistering on his face and distal upper and lower extremities. Subepidermal blisters containing neutrophils and eosinophils visualized on histology supported the diagnosis of linear IgA bullous dermatosis of childhood (LABDC). The dermatosis presents with vesicles and tense blisters in an annular distribution, erythematous papules, and/or excoriated plaques. Histopathology shows subepidermal blisters with a neutrophilic infiltrate in the dermis, mainly concentrated at the tips of dermal papillae in the early stage of the disease, which can be mistaken for the pattern of neutrophilic infiltration as seen in dermatitis herpetiformis. Dapsone is the treatment of choice, which is started at a dosage of 0.5mg/kg/day. Linear IgA bullous dermatosis of childhood is a rare autoimmune disease that can be mistaken for other conditions with similar presentations but should always be considered in the differential diagnosis of children with blistering.

Porokeratosis Plantaris, Palmaris et Disseminata Caused by Con- genital Pathogenic Variants in the MVD Gene and Loss of Hetero-zygosity in Affected Skin.

Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. However, the molecular mechanism leading to development of porokeratosis plantaris, palmaris et disseminata is not known. This study analysed a cohort of 4 patients with linear porokeratosis and 3 patients with porokeratosis plantaris, palmaris et disseminata, and performed mutation analyses of DNA extracted from blood samples and skin biopsies. All of the study patients carried the heterozygous germline variant c.70+5G>A in the MVD gene. Loss of heterozygosity due to a second hit mutation was found in affected skin of 3 patients with linear porokeratosis and 2 patients with porokeratosis plantaris, palmaris et disseminata. These results suggest that porokeratosis plantaris, palmaris et disseminata shares the same pathogenetic mechanism as other porokeratosis subtypes and belongs to the phenotypic spectrum of MVD-associated porokeratosis.

A Family with Palmar and Plantar Hyperkeratosis: A Quiz.

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Bullous autoimmune dermatoses.

Pathophysiologically, bullous autoimmune dermatoses are caused by autoantibodies directed against adhesion molecules or structural proteins of the skin and mucous membranes, clinically resulting in blister formation. Depending on the respective target proteins of the autoimmune response and their location in the skin, a distinction is made between intraepidermal (pemphigus disorders), junctional (pemphigoid disorders), and subepidermal (epidermolysis bullosa acquisita, dermatitis herpetiformis) autoimmune blistering diseases. The most common bullous autoimmune dermatosis, bullous pemphigoid is characterized by marked clinical variability and intense pruritus. Predominantly affecting elderly individuals, there has been a significant increase in its incidence in recent years. While mucosal lesions occur in less than 30 % of bullous pemphigoid patients, the second most common bullous autoimmune dermatosis, pemphigus vulgaris, typically presents with oral erosions as the predominant and - frequently - initial symptom. Its onset is usually in the 4th to 6th decade of life. Scarring is typically found in subepidermal blistering disorders such as epidermolysis bullosa acquisita or mucous membrane pemphigoid. Diagnosis is based on clinical and histological findings as well as direct and indirect immunofluorescence and detection of circulating autoantibodies. Although a number of controlled clinical trials have been conducted in recent years, treatment of bullous autoimmune disorders is still primarily based on clinical experience. Therapeutic options include topical and systemic corticosteroids as well as adjuvant immunosuppressants. Recalcitrant cases may require treatment with immunoadsorption, intravenous immunoglobulins, or the monoclonal anti-CD20 antibody rituximab.

Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4+ T cells specific for an epitope within the extracellular domain of DSG3, DSG3(206-220), were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3(206-220) and DSG3(378-392), correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLA-DRB1∗04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV.

Skin-infiltrating T cells display distinct inflammatory signatures in lichen planus, bullous pemphigoid and pemphigus vulgaris.

Introduction: We here thought to dissect the inflammatory signature in lesions of three skin disorders, which show a common adaptive immune response against autoantigens of the skin but are characterized by diverging clinical phenotypes. Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are type-2-dependent, IgG autoantibody-driven blistering disorders of mucous membranes and skin, which target desmoglein (Dsg)3 and bullous pemphigoid (BP)180, respectively. In contrast, lichen planus (LP) is a common chronic inflammatory disease of the skin and mucous membranes with a pronounced dermal T cell infiltrate. We previously identified peripheral type 1 and 17 T cell responses against Dsg3 and BP180 in a cohort of LP patients strongly suggesting that the underlying inflammatory T cell signature may drive the evolving phenotype. Methods: Paraffin-embedded skin biopsies from well-characterized patients with LP (n=31), BP (n=19), PV (n=9), and pemphigus foliaceus (PF) (n=2) were analysed. Areas with the most prominent inflammatory infiltrate were excised with punch biopsies and tissue microarrays (TMA) containing multiple biopsies were created. Using multicolor immunofluorescence, the inflammatory infiltrate was stained with antibodies against multiple cellular markers, i. e. CD3ϵ, CD4, CD15, TCR-δ, the cytokine IL-17A, and the transcription factors, T-bet and GATA-3. Results: In LP, there was a higher number of CD4+ T cells expressing T-bet compared to GATA-3. In contrast, CD4+ T cells in PV and BP skin lesions more frequently expressed GATA-3 than T-bet. IL-17A+ cells and IL-17A+ T cells were found to a similar extent in all the three disorders. IL-17A+ granulocytes were more predominant in BP than in LP or PV. Of note, the majority of IL-17A+ cells in LP were neither T cells nor granulocytes. Discussion: Our findings in inflammatory skin infiltrates clearly show a predominant type 1 signature in LP in contrast to a preponderance of type 2 T cells in PV and BP. In contrast to LP, granulocytes and to a much lesser extent CD3+ T cells were a cellular source of IL-17A in BP and PV. These data strongly suggest that different inflammatory cell signatures drive evolving clinically diverse phenotypes of LP, PV and BP despite common target antigens of the skin.

Clinicians' pearls and myths in pemphigus.

Pemphigus comprises a heterogeneous group of autoimmune blistering diseases, which can affect both skin and mucous membranes, especially oral mucosa. This group of diseases shows usually a chronic-relapsing course. Since pemphigus is a rare disease, the diagnosis is often delayed, because it is based upon the recognition of consistent clinical, histologic, and direct immunofluorescence findings, as well as indirect immunofluorescence, and/or enzyme-linked immunosorbent assay. Usually the patients are treated for multiple other conditions before starting the correct therapy, leading to a critical reduction of the patients' quality of life. This review is a succinct compilation of pearls gathered from clinical experience in pemphigus and the myths that may have influenced everyday practice but have been proven false. This review provided a selection of such dilemmas and controversies, focusing on myths and pearls that can help young dermatologist in the clinic, while also dispelling them.