Publications by authors named "Jemima E Mellerio"

72 Publications

Cutaneous Squamous Cell Carcinoma in Epidermolysis Bullosa: a 28-year Retrospective Study.

Acta Derm Venereol 2021 Jul 7. Epub 2021 Jul 7.

St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinomas-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinomas of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.
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http://dx.doi.org/10.2340/00015555-3875DOI Listing
July 2021

Clinical practice guidelines: Oral health care for children and adults living with epidermolysis bullosa.

Spec Care Dentist 2020 Nov;40 Suppl 1:3-81

Birmingham Children's Hospital, UK.

Background: Inherited epidermolysis bullosa (EB) is a genetic disorder characterized by skin fragility and unique oral features.

Aims: To provide (a) a complete review of the oral manifestations in those living with each type of inherited EB, (b) the current best practices for managing oral health care of people living with EB, (c) the current best practices on dental implant-based oral rehabilitation for patients with recessive dystrophic EB (RDEB), and (d) the current best practice for managing local anesthesia, principles of sedation, and general anesthesia for children and adults with EB undergoing dental treatment.

Methods: Systematic literature search, panel discussion including clinical experts and patient representatives from different centers around the world, external review, and guideline piloting.

Results: This article has been divided into five chapters: (i) general information on EB for the oral health care professional, (ii) systematic literature review on the oral manifestations of EB, (iii) oral health care and dental treatment for children and adults living with EB-clinical practice guidelines, (iv) dental implants in patients with RDEB-clinical practice guidelines, and (v) sedation and anesthesia for adults and children with EB undergoing dental treatment-clinical practice guidelines. Each chapter provides recommendations on the management of the different clinical procedures within dental practice, highlighting the importance of patient-clinician partnership, impact on quality of life, and the importance of follow-up appointments. Guidance on the use on nonadhesive wound care products and emollients to reduce friction during patient care is provided.

Conclusions: Oral soft and hard tissue manifestations of inherited EB have unique patterns of involvement associated with each subtype of the condition. Understanding each subtype individually will help the professionals plan long-term treatment approaches.
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http://dx.doi.org/10.1111/scd.12511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756753PMC
November 2020

Dermatofibrosarcoma protuberans (DFSP) in children: A combined multidisciplinary approach.

Pediatr Dermatol 2021 Jan 11;38(1):233-236. Epub 2020 Nov 11.

Department of Plastic Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Dermatofibrosarcoma protuberans (DFSP) is rare, comprising (1%-6%) of all sarcomas. The incidence is less than one per million before the age of 20. It is a locally aggressive tumor with a low risk of metastasis. We share our experience in the management of three pediatric patients with complex cases of DFSP in a combined surgical approach involving plastic and dermatologic surgery, using the slow Mohs micrographic surgery technique.
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http://dx.doi.org/10.1111/pde.14425DOI Listing
January 2021

Epidermolysis bullosa.

Nat Rev Dis Primers 2020 09 24;6(1):78. Epub 2020 Sep 24.

Epidermolysis Bullosa Unit, Department of Dermatology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, UK.

Epidermolysis bullosa (EB) is an inherited, heterogeneous group of rare genetic dermatoses characterized by mucocutaneous fragility and blister formation, inducible by often minimal trauma. A broad phenotypic spectrum has been described, with potentially severe extracutaneous manifestations, morbidity and mortality. Over 30 subtypes are recognized, grouped into four major categories, based predominantly on the plane of cleavage within the skin and reflecting the underlying molecular abnormality: EB simplex, junctional EB, dystrophic EB and Kindler EB. The study of EB has led to seminal advances in our understanding of cutaneous biology. To date, pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion. Precise diagnosis is reliant on correlating clinical, electron microscopic and immunohistological features with mutational analyses. In the absence of curative treatment, multidisciplinary care is targeted towards minimizing the risk of blister formation, wound care, symptom relief and specific complications, the most feared of which - and also the leading cause of mortality - is squamous cell carcinoma. Preclinical advances in cell-based, protein replacement and gene therapies are paving the way for clinical successes with gene correction, raising hopes amongst patients and clinicians worldwide.
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http://dx.doi.org/10.1038/s41572-020-0210-0DOI Listing
September 2020

Emergency management in epidermolysis bullosa: consensus clinical recommendations from the European reference network for rare skin diseases.

Orphanet J Rare Dis 2020 06 6;15(1):142. Epub 2020 Jun 6.

Dermatology Department, reference Centre MAGEC, Necker- Enfants Malades Hospital, Paris-Centre University, Paris, France.

Epidermolysis bullosa (EB) comprises a group of genetic disorders with the hallmark of fragility of the skin and mucosal surfaces. The severity of different types of EB varies markedly as does the occurrence of extra-cutaneous involvement and complications. A number of emergency situations may occur in the context of EB including obstruction to oral intake from oral or esophageal blisters or scarring, acute airway obstruction, acute urinary retention, sepsis and corneal erosions. Whilst general management principles apply in each of these settings, specific considerations are essential in managing EB to avoid undue trauma or damage to delicate tissues. These recommendations have been developed from a literature review and consensus from experts of the European Network for Rare Skin Disorders (ERN-Skin) to aid decision-making and optimize clinical care by non-EB expert health professionals encountering emergency situations in babies, children and adults with EB.
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http://dx.doi.org/10.1186/s13023-020-01403-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276067PMC
June 2020

Meeting Report: The First Global Congress on Epidermolysis Bullosa, EB2020 London: Toward Treatment and Cure.

J Invest Dermatol 2020 09 16;140(9):1681-1687. Epub 2020 May 16.

Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.05.078DOI Listing
September 2020

Ectodermal dysplasia-skin fragility syndrome: Two new cases and review of this desmosomal genodermatosis.

Exp Dermatol 2020 06 25;29(6):520-530. Epub 2020 May 25.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.

Background: Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997.

Methods: To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019.

Results: Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections.

Conclusion: These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.
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http://dx.doi.org/10.1111/exd.14096DOI Listing
June 2020

The adverse effect profile of acitretin in a pediatric dermatology population-Longitudinal cohort study and recommendations for monitoring.

J Am Acad Dermatol 2020 Dec 1;83(6):1779-1781. Epub 2020 Apr 1.

Great Ormond St Hospital for Children and UCL GOS Institute of Child Health, London, United Kingdom; Mosaicism and Precision Medicine Laboratory, The Francis Crick Institute, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.03.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171276PMC
December 2020

Pseudoporphyria induced by ultraviolet radiation.

Australas J Dermatol 2020 May 10;61(2):177-179. Epub 2019 Dec 10.

St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/ajd.13212DOI Listing
May 2020

Homozygous Nonsense Mutation in DSC3 Resulting in Skin Fragility and Hypotrichosis.

J Invest Dermatol 2020 06 29;140(6):1285-1288. Epub 2019 Nov 29.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.10.015DOI Listing
June 2020

Phase I/II open-label trial of intravenous allogeneic mesenchymal stromal cell therapy in adults with recessive dystrophic epidermolysis bullosa.

J Am Acad Dermatol 2020 Aug 28;83(2):447-454. Epub 2019 Nov 28.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK. Electronic address:

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder due to a lack of type VII collagen. At present, treatment is mainly supportive.

Objectives: To determine whether intravenous allogeneic bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) are safe in RDEB adults and if the cells improve wound healing and quality of life.

Methods: We conducted a prospective, phase I/II, open-label study recruiting 10 RDEB adults to receive 2 intravenous infusions of BM-MSCs (on day 0 and day 14; each dose 2-4 × 10 cells/kg).

Results: BM-MSCs were well tolerated with no serious adverse events to 12 months. Regarding efficacy, there was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch. One individual showed a transient increase in type VII collagen.

Limitations: Open-label trial with no placebo.

Conclusions: MSC infusion is safe in RDEB adults and can have clinical benefits for at least 2 months.
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http://dx.doi.org/10.1016/j.jaad.2019.11.038DOI Listing
August 2020

Generation and Clinical Application of Gene-Modified Autologous Epidermal Sheets in Netherton Syndrome: Lessons Learned from a Phase 1 Trial.

Hum Gene Ther 2019 09 5;30(9):1067-1078. Epub 2019 Aug 5.

Infection, Immunity and Inflammation Programme, UCL GOS Institute of Child Health, London, United Kingdom.

Netherton syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in . It is a debilitating condition with notable mortality in the early years of life. There is no curative treatment. We undertook a nonrandomized, open-label, feasibility, and safety study using autologous keratinocytes transduced with a lentiviral vector encoding under the control of the human involucrin promoter. Six NS subjects were recruited, and gene-modified epithelial sheets were successfully generated in three of five subjects. The sheets exhibited expression of correctly sized lympho-epithelial Kazal-type-related inhibitor (LEKTI) protein after modification. One subject was grafted with a 20 cm gene-modified graft on the left anterior thigh without any adverse complications and was monitored by serial sampling for 12 months. Recovery within the graft area was compared against an area outside by morphology, proviral copy number and expression of the encoded protein, LEKTI, and its downstream target kallikrein 5, which exhibited transient functional correction. The study confirmed the feasibility of generating lentiviral gene-modified epidermal sheets for inherited skin diseases such as NS, but sustained LEKTI expression is likely to require the identification, targeting, and engraftment of long-lived keratinocyte stem cell populations for durable therapeutic effects. Important learning points for the application of gene-modified epidermal sheets are discussed.
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http://dx.doi.org/10.1089/hum.2019.049DOI Listing
September 2019

Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosa.

JCI Insight 2019 06 6;4(11). Epub 2019 Jun 6.

Department of Haematological Medicine, King's College London, The Rayne Institute, London, United Kingdom.

BACKGROUNDRecessive 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.METHODSIn this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 106 cells/cm2 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.RESULTSGene-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.CONCLUSIONTo 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 REGISTRATIONClincalTrials.gov NCT02493816.FUNDINGCure 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.
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http://dx.doi.org/10.1172/jci.insight.126243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629162PMC
June 2019

Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.

Clin Cancer Res 2019 06 7;25(11):3384-3391. Epub 2019 Mar 7.

Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.

Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC and .

Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib.

Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185613PMC
June 2019

APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa.

Sci Transl Med 2018 08;10(455)

Fundación DEBRA Chile, Santiago 7760099, Chile.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.
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http://dx.doi.org/10.1126/scitranslmed.aas9668DOI Listing
August 2018

Clinical subtypes and molecular basis of epidermolysis bullosa in Kuwait.

Int J Dermatol 2018 Sep 16;57(9):1058-1067. Epub 2018 Jul 16.

St. John's Institute of Dermatology, King's College London, Guy's Campus, London, UK.

Background: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous blistering skin disease, but in countries such as Kuwait, there are very limited data on the clinical and molecular pathology of EB. To improve understanding of EB in Kuwait, we report the experience of a local tertiary referral center over a 17.5 year period (January 2000-June 2017) in establishing clinical and molecular diagnoses.

Methods: Review of hospital records and diagnostic reports. Individual cases were diagnosed by combinations of clinical assessment, skin biopsy (immunohistochemistry and transmission electron microscopy), Sanger sequencing of EB genes, and whole exome sequencing.

Results: Fifty-four families with EB were registered with the clinic over this period, 41 of whom (84 patients) participated in diagnostic studies. Thirty-seven of these 41 families had consanguineous marriages; 34 had recessive forms of EB, while only seven had dominant subtypes. Recurrent mutations were observed in epidermal dystonin, transglutaminase 5, and type VII collagen.

Conclusions: The prevalence of EB in Kuwait is approximately three times that of internationally cited rates with an over-representation of autosomal recessive variants. Establishing the molecular basis of EB in Kuwait with accurate diagnostic subtyping provides a basis for determining healthcare requirements and improving patient management of EB.
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http://dx.doi.org/10.1111/ijd.14099DOI Listing
September 2018

Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: the identification of mechanisms of differential sensitivity.

Oncotarget 2018 Apr 17;9(29):20265-20281. Epub 2018 Apr 17.

Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.

Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics. These agents can selectively kill cSCC cells but there are variations in the pattern of cSCC cell line sensitivity/resistance. Variations in the responses to proteasome inhibitors are associated with differences in the specificity of the inhibitors for the three proteolytic activities of the proteasome. There is greater selectivity for killing cSCC cells compared to normal keratinocytes with a pulse of proteasome inhibitor treatment than with a more extended exposure. We provide evidence that c-MYC-dependent NOXA upregulation confers susceptibility to a short incubation with proteasome inhibitors by priming cSCC cells for rapid BAK-dependent death. We observed that bortezomib-resistant cSCC cells can be sensitive to MLN7243-induced death. Low expression of the ubiquitin E1 UBA1/UBE1 participates in conferring susceptibility to MLN7243 by increasing sensitivity to MLN7243-mediated attenuation of ubiquitination. This study supports further investigation of the potential of proteasome and ubiquitin E1 inhibition for cSCC therapy. Direct delivery of inhibitors could facilitate adequate exposure of skin cancers.
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http://dx.doi.org/10.18632/oncotarget.24750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945540PMC
April 2018

Extracellular Vesicles as Biomarkers for the Detection of a Tumor Marker Gene in Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.

J Invest Dermatol 2018 05 2;138(5):1197-1200. Epub 2017 Dec 2.

EB House Austria, Research Program for the Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2017.11.022DOI Listing
May 2018

Considerations in surgical management of a Buschke-Lowenstein tumor in Netherton syndrome: A case report.

Pediatr Dermatol 2017 Nov;34(6):e328-e330

Department of Dermatology, Great Ormond Street Hospital, London, UK.

Netherton syndrome is an autosomal recessive ichthyosis caused by mutations in SPINK5, with the classic triad of linearis circumflexa, trichorrhexis invaginata, and atopy. There are few reports of surgical management in individuals with Netherton syndrome and clinicians may be reluctant to operate for fear of wound-healing complications. This report describes a pediatric case of a Buschke-Lowenstein tumor of the natal cleft in a patient with Netherton syndrome that had failed to respond to medical management. We reviewed the literature for previous cases of surgery in individuals with Netherton syndrome using MEDLINE and PubMed searches. Our patient underwent surgery to remove the lesion without complication. Using conventional dressings and topical negative-pressure therapy, the wound was managed and healed within a reasonable time frame despite the underlying skin condition. This case indicates that surgery and topical negative-pressure therapy is a safe and reasonable treatment for individuals with Netherton syndrome.
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http://dx.doi.org/10.1111/pde.13292DOI Listing
November 2017

A Keratotic Papule on the Ear of a 10-Year-Old Girl.

Pediatr Dermatol 2017 Mar;34(2):195-196

Department of Dermatology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/pde.13112DOI Listing
March 2017

Mutations in KLHL24 Add to the Molecular Heterogeneity of Epidermolysis Bullosa Simplex.

J Invest Dermatol 2017 06 19;137(6):1378-1380. Epub 2017 Jan 19.

St John's Institute of Dermatology, King's College London (Guy's Campus), London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2017.01.004DOI Listing
June 2017

Epidermolysis Bullosa with Pyloric Atresia and Significant Urologic Involvement.

Pediatr Dermatol 2017 Jan 4;34(1):e61-e64. Epub 2016 Nov 4.

Dell Medical School, University of Texas, Austin, Texas.

Epidermolysis bullosa (EB) is a rare inherited disease that causes epidermal fragility, blistering, and erosions. EB results from a variety of mutations in proteins of the skin and mucous membranes of the body. Mutations in plectin a protein involved in hemidesmosome integrity and function, are associated with subtypes of EB, including EB with pyloric atresia and EB with muscular dystrophy. We present two cases of EB with significant urologic involvement resulting from mutations in plectin.
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http://dx.doi.org/10.1111/pde.13026DOI Listing
January 2017

Large Intragenic KRT1 Deletion Underlying Atypical Autosomal Dominant Keratinopathic Ichthyosis.

J Invest Dermatol 2016 10 25;136(10):2095-2098. Epub 2016 Jun 25.

St John's Institute of Dermatology, King's College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2016.06.016DOI Listing
October 2016

Ichthyosis Prematurity Syndrome: From Fetus to Adulthood.

JAMA Dermatol 2016 09;152(9):1055-8

St John's Institute of Dermatology, King's College London, Guy's Campus, London, England.

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http://dx.doi.org/10.1001/jamadermatol.2016.1187DOI Listing
September 2016

The Frequency of Signs of Meibomian Gland Dysfunction in Children with Epidermolysis Bullosa.

Ophthalmology 2016 05 12;123(5):991-9. Epub 2016 Feb 12.

Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, United Kingdom; Developmental Biology Unit, Institute of Child Health, University College London, London, United Kingdom; UPMC Childrens Eye Center, Childrens Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Purpose: To determine the frequency of meibomian gland dysfunction (MGD) in children with epidermolysis bullosa (EB).

Design: Hospital-based cross-sectional study.

Participants: One hundred five children with different forms of EB.

Methods: Prospective ophthalmic examination of children with EB presenting over seventeen months including meibomian gland assessment using a recognized classification.

Main Outcome Measures: Frequency of MGD.

Results: One hundred five children were recruited, 8.6% with junctional EB, 34.3% with simplex EB, 34.3% with autosomal recessive dystrophic EB, and 22.9% autosomal dominant dystrophic EB. Mean age was 7.42 years (range, 0.08-17.75 years). Ninety-two children (87.62%) demonstrated 1 or more features of MGD.

Conclusions: Most children with EB exhibit signs of MGD. To the best of our knowledge, this is the first prospective ocular surface evaluation in children with EB to include lid margin evaluation using a recognized classification system. Our findings help explain some of the ocular surface anomalies seen in children with EB.
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http://dx.doi.org/10.1016/j.ophtha.2015.12.040DOI Listing
May 2016

Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.

J Invest Dermatol 2014 Oct 1;134(10):2570-2578. Epub 2014 Apr 1.

St John's Institute of Dermatology, King's College London, London, UK; The Centre for Dermatology and Genetic Medicine, University of Dundee, Dundee, UK. Electronic address:

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.
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http://dx.doi.org/10.1038/jid.2014.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090136PMC
October 2014

Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification.

J Am Acad Dermatol 2014 Jun 29;70(6):1103-26. Epub 2014 Mar 29.

Istituto Dermopatico dell' Immacolata, IDI-IRCCS, Rome, Italy.

Background: Several new targeted genes and clinical subtypes have been identified since publication in 2008 of the report of the last international consensus meeting on diagnosis and classification of epidermolysis bullosa (EB). As a correlate, new clinical manifestations have been seen in several subtypes previously described.

Objective: We sought to arrive at an updated consensus on the classification of EB subtypes, based on newer data, both clinical and molecular.

Results: In this latest consensus report, we introduce a new approach to classification ("onion skinning") that takes into account sequentially the major EB type present (based on identification of the level of skin cleavage), phenotypic characteristics (distribution and severity of disease activity; specific extracutaneous features; other), mode of inheritance, targeted protein and its relative expression in skin, gene involved and type(s) of mutation present, and--when possible--specific mutation(s) and their location(s).

Limitations: This classification scheme critically takes into account all published data through June 2013. Further modifications are likely in the future, as more is learned about this group of diseases.

Conclusion: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and molecular features of each EB subtype, and has sufficient flexibility incorporated in its structure to permit further modifications in the future.
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http://dx.doi.org/10.1016/j.jaad.2014.01.903DOI Listing
June 2014