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Plaque-like myofibroblastic tumour (PLMT) is a rare skin condition which presents in childhood and infancy as a nodular fibrous plaque. Including our case, there are currently only 14 cases reported in the literature. Although it represents a well-defined clinicopathological diagnosis, there is significant under-reporting of this condition secondary to under-recognition and potential misdiagnosis as dermatofibroma.

We present the case of a 10-year-old boy who was admitted with 3 months of episodic febrile neutropenia and a new petechial rash. Routine bloods identified neutropenia, thrombocytopenia, and a raised alanine aminotransferase. The dermatology team was consulted in light of the symmetrical petechial eruption of the upper torso. A punch biopsy of the lesion was consistent with early capillaritis. The results showed superficial dermal red blood cell extravasation with mild perivascular lymphohistiocytic inflammatory infiltrate. There was no evidence of an atypical lymphoid infiltrate in the skin biopsy. An initial bone marrow aspirate showed an abnormal mature T-cell population consisting of CD4 and CD8 T cells with gamma-delta positivity. Karyotyping was also done, which demonstrated isochromosome 7q. These findings were consistent with a diagnosis of hepatosplenic T-cell lymphoma (HSTL). The patient underwent fourth-line chemotherapy due to refractory relapsing disease but sadly passed away within 12 months of diagnosis. HSTL is a rare and aggressive subset of peripheral T-cell lymphoma. Prognosis is poor with a median survival of1 year from diagnosis. However, reports suggest improved outcomes if intensive, early, high-dose chemotherapy is used alongside hematopoietic stem cell transplantation. Therefore, there is an impetus to attain early diagnosis for aggressive early treatment and improved patient outcomes. Capillaritis, presenting as asymptomatic nonpalpable purpura, can be a rare presenting feature of HSTL. Dermatologists could play a pivotal role in the early recognition of this rare but aggressive hematological malignancy and promote prompt treatment resulting in better patient outcomes.

Netherton syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in SPINK5. It is a debilitating condition with notable mortality in the early years of life. There is no cura...

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS: In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 10(6) cells/cm(2) of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS: Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION: To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION: ClincalTrials.gov NCT02493816. FUNDING: Cure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and Fondation René Touraine Short-Exchange Award.

Mutations in the keratin 10 gene (KRT10) have been shown to underlie several forms of epidermolytic ichthyosis (EI), including generalized, annular and naevoid variants. We investigated an autosomal dominant pedigree with ichthyosis in which there was intrafamilial clinical heterogeneity, with the affected individual family members presenting with features of either erythrokeratoderma progressiva, annular EI, localized or superficial EI, or more generalized EI. Sanger sequencing identified a new heterozygous missense mutation (c.457C>A; p.Leu153Met) in KRT10 in all affected individuals. No additional mutations were identified in the genes for keratin 1 (KRT1) keratin 2 (KRT2), connexin 31 (GJB3) or connexin 30.3 (GJB4) that might account for the clinical heterogeneity seen in this family. Our findings illustrate the intrafamilial variability in phenotype and diverse clinical presentations that can occur in EI resulting from a single mutation in KRT10.

Netherton syndrome (NS) is a serious inherited skin disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal type 5) which encodes for a serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). Patients with NS have defective keratinization, hair shaft defects, recurrent infections, atopy and a predisposition to skin malignancies. Historically, one in ten infants has died before their first birthday. Currently there are no proven treatments to cure this condition. A SIN-lentiviral vector encoding the codon optimized SPINK5 gene under the control of a 572bp element derived from the human involucrin promoter (INVO) can confer compartment specific LEKTI expression in NS keratinocytes with restoration of normal skin architecture. Here we detail a study protocol for a phase I trial for feasibility and safety evaluations of autologous epidermal sheets generated from ex-vivo gene corrected keratinocyte stem cells, which will be grafted onto patients with mutation proven NS.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited blistering skin diseases. Severe forms of EB are associated with increased morbidity and mortality, and there is currently no effective treatment. To combat severe complications of EB, such as chronic erosions, scarring and malignancy, effective therapy needs to be given systemically and at an early age. One recent therapeutic advancement has been a clinical trial of whole bone marrow (BM) transplantation in children with the dystrophic form of EB. This led to correction of the inherent skin basement membrane defect and better skin integrity in some individuals. The challenge now is to precisely identify which BM cells contribute to skin recovery and what mechanisms are involved in tissue regeneration. An improved understanding of the key aspects of BM skin repair is likely to lead to significant health improvements for patients with EB and other skin diseases.

In the inherited blistering skin disease, recessive dystrophic epidermolysis bullosa (RDEB), there is clinical heterogeneity with variable scarring and susceptibility to malignancy. Currently, however, there are few biochemical markers of tissue inflammation or disease progression. We assessed whether the non-histone nuclear protein, high mobility group box 1 (HMGB1), which is released from necrotic cells (including keratinocytes in blister roofs), might be elevated in RDEB and whether this correlates with disease severity. We measured serum HMGB1 by ELISA in 26 RDEB individuals (median 21.0 ng/ml, range 3.6-54.9 ng/ml) and 23 healthy controls (median 3.6, range 3.4-5.9 ng/ml) and scored RDEB severity using the Birmingham Epidermolysis Bullosa Severity Score (BEBSS; mean 34/100, range 8-82). There was a positive relationship between the BEBSS and HMGB1 levels (r = 0.54, P = 0.004). This study indicates that serum HMGB1 levels may represent a new biomarker reflecting disease severity in RDEB.

Skin is an amenable organ for gene replacement and gene editing therapeutics. Its accessibility makes it well-suited for direct topical gene delivery, grafting of genetically corrected cells, and monitoring of possible adverse events. Monogenic recessive disorders with a clinically severe or life-threatening phenotype provide the best candidate diseases for the introduction of a single normal copy of the gene into the target cell, usually keratinocytes. Preclinical studies have shown impressive results in terms of gene correction using both in vivo and ex vivo approaches. The clinical application of gene replacement or genomic editing as potential therapies for inherited skin disorders, however, has been held back by the inadequacy of delivery vectors and concerns from regulatory agencies regarding safety; thus translation to clinical trials has been slow. Over the past 15 years, cell culture and animal models have shown efficient gene correction techniques as preludes to treat inherited skin disorders such as junctional epidermolysis bullosa, dystrophic epidermolysis bullosa, xeroderma pigmentosum, lamellar ichthyosis and Netherton syndrome, but so far only one patient has been treated in a clinical trial. This article reviews the current status of gene therapies for patients with inherited skin diseases and explores future perspectives.

Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.

Background The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas but only rarely in primary cutaneous follicle center cell lymphomas (PCFCL). Recent studies have postulated that the translocation is more prevalent in PCFCL than previously described and that it might be a molecular prognostic marker. Objectives The purpose of our study was to analyze cases of PCFCL for the presence of a t(14;18) translocation using fluorescence in situ hybridization to detect balanced translocations involving either the BCL2 or MALT1 loci and to correlate the results with growth pattern, immunophenotype, and clinical outcome. Method In all, 57 patients with PCFCL were extracted from our cutaneous lymphoma database. Retrospective analysis of clinical parameters including lesion type, location, diagnostic stage, lactate dehydrogenase, initial treatment, relapse rate, and survival was performed. Results In all, 57 patients with PCFCL were included in this study. We detected 1 BCL2 chromosomal amplification, 4 translocations of BCL2, and 1 IGH/MALT1 translocation. Limitations This was a case series retrospective study. Conclusions PCFCL has an excellent 5-year overall survival (100% disease-specific survival). Chromosomal abnormalities of either BCL2 or MALT1 were detected in 10% of cases but do not correlate with a specific immune pathology or clinical outcome.

A 33 year old woman at 40 weeks’ gestation of her first pregnancy presented with an itchy rash. This had started 14 days earlier with a few red patches on her lower abdomen but extended to involve her thighs and upper arms. The rash was increasingly pruritic. She reported gluten insensitivity (coeliac disease not confirmed) and had no dermatological or atopic history. The pregnancy had been uneventful until this point. She took no regular drugs and had not used any topical preparations. Her rash on clinical examination was as shown in the photograph.⇓ ### 1 How would you describe the rash? #### Short answer An erythematous papular rash has spared the periumbilical region but in places has formed areas of confluent urticated erythema, especially at the striae distensae. #### Long answer An erythematous papular rash has spared the periumbilical region but in places has coalesced to form areas of confluent urticated erythema, especially at the striae distensae (“stretch marks”). The linear hyperpigmentation along the mid-line of the abdomen, known as the linea nigra, is a physiological phenomenon commonly seen in pregnancy.1 ### 2 What is your diagnosis? #### Short answer A papulo-urticarial rash developing in the third trimester of a first pregnancy, originating within the striae distensae and sparing the umbilicus, is typical of polymorphic eruption of pregnancy (PEP). #### Long answer PEP affects about one in 160 pregnancies and commonly occurs in the third trimester (91% of cases) of primigravid women (73%).2 3 It classically presents with polymorphic erythema, papules, or vesicles (that can be urticated) that arise within the striae distensae of the abdomen and spare the peri-umbilical region, face, and acral sites.4 Less commonly the rash can become generalised, and rarely the vesicles form larger bullae.3 …

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-function mutations in COL7A1, the gene encoding type VII collagen (C7), a protein central to anchoring fibril formation at the dermal-epidermal junction (DEJ). Presently there are no curative treatments for this condition. We have been developing the gene therapy protocol for locally injection of lentiviral mediated COL7A1 gene-modified autologous fibroblasts into the patients with RDEB. Primary fibroblasts were isolated from a 6mm skin biopsy. Cells are expanded and transduced with a GMP compliant lenti-viral vector containing codon optimised COL7A1 gene cDNA under the control of the human PGK promoter. Transduced cells were further expended to reach appropriate cell numbers and cryopreserved until patients are ready. Scale up studies carried out in our GMP compliance laboratory showed C7 expression and stable integration of vector into cells. In-situ immunostaining and western blot analysis confirmed the expression of collagen VII protein (C7) not only in transduced RDEB fibroblasts but also in the culture media, indicating there is secreted C7 from transduced cells.The primary objective of our proposed Phase-I study is to determine the safety and tolerability of treatment with autologous gene modified cells administered to RDEB patients. Fibroblasts expressing codon-optimised COL7A1 will be injected intra-dermally in 5-10 adults with RDEB. The secondary objectives are to assess the efficacy of this treatment and its impact on skin and reversion of gene expression. Each study participant will receive three intradermal injections of ex-vivo transduced autologous fibroblasts expressing codon-optimised COL7A1 as the IMP and three intradermal injections of non-transduced autologous fibroblasts as control. Each injection (both IMP and control) will be administered into separate 1cm2 areas of intact skin sites. Participants will be followed up with study interventions for a total of 36-month period at various time points. If successful, a similar approach could be used to modify autologous epidermal sheets for localised treatment of blisters as well as systemic cell therapies.

There is only a weak association between the degree of anaemia and severity of fatigue in cancer patients. It has been hypothesised that there may be functional changes in the erythrocytes or haemoglobin of cancer patients and that this may result in fatigue even in the presence of a “normal” or “low normal” haematocrit. The purpose of the study was to investigate the relationship between oxyhaemoglobin dissociation and fatigue in patients with cancer and to compare oxyhaemoglobin dissociation between cancer patients and healthy controls. A heterogeneous group of patients with cancer (n=22) and a control group of healthy subjects without cancer (n=28) were studied. Subjects completed a fatigue questionnaire [the Functional Assessment of Cancer Therapy Fatigue (FACT-F) scale] and provided 10 ml of blood for analysis. Specimens were analysed to determine the partial pressure of oxygen at which 50% haemoglobin saturation occurred (P50) and were also sent for routine haematological and biochemical analysis. No differences were found between the oxyhaemoglobin dissociation curves of patients with cancer and controls. There was no significant correlation between fatigue severity and P50 in either patients or controls. There is no evidence to support the hypothesis that cancer-related fatigue is due to differences in oxyhaemoglobin dissociation.

Harnessing the regenerative capacity of keratinocytes and fibroblasts from human skin has created new opportunities to develop cell-based therapies for patients. Cultured cells and bioengineered skin products are being used to treat patients with inherited and acquired skin disorders associated with defective skin, and further clinical trials of new products are in progress. The capacity of extracutaneous sources of cells such as bone marrow is also being investigated for its plasticity in regenerating skin, and new strategies, such as the derivation of inducible pluripotent stem cells, also hold great promise for future cell therapies in dermatology. This article reviews some of the preclinical and clinical studies and future directions relating to cell therapy in dermatology, particularly for inherited skin diseases associated with fragile skin and poor wound healing.