Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

TRIPLE C reporting principles for case study evaluations of the role of context in complex interventions.

BACKGROUND: Guidance and reporting principles such as CONSORT (for randomised trials) and PRISMA (for systematic reviews) have greatly improved the reporting, discoverability, transparency and consistency of published research. We sought to develop similar guidance for case study evaluations undertaken to explore the influence of context on the processes and outcomes of complex interventions. METHODS: A range of experts were recruited to an online Delphi panel, sampling for maximum diversity in disciplines (e.g. public health, health services research, organisational studies), settings (e.g. country), and sectors (e.g. academic, policy, third sector). To inform panel deliberations, we prepared background materials based on: [a] a systematic meta-narrative review of empirical and methodological literatures on case study, context and complex interventions; [b] the collective experience of a network of health systems and public health researchers; and [c] the established RAMESES II standards (which cover one kind of case study). We developed a list of topics and issues based on these sources and encouraged panel members to provide free text comments. Their feedback informed development of a set of items in the form of questions for potential inclusion in the reporting principles. We circulated these by email, asking panel members to rank each potential item twice (for relevance and validity) on a 7-point Likert scale. This sequence was repeated twice. RESULTS: We recruited 51 panel members from 50 organisations across 12 countries, who brought experience of a range of case study research methods and applications. 26 completed all three Delphi rounds, reaching over 80% consensus on 16 items covering title, abstract, definitions of terms, philosophical assumptions, research question(s), rationale, how context and complexity relates to the intervention, ethical approval, empirical methods, findings, use of theory, generalisability and transferability, researcher perspective and influence, conclusions and recommendations, and funding and conflicts of interest. CONCLUSION: The 'Triple C' (Case study, Context, Complex interventions) reporting principles recognise that case studies are undertaken in different ways for different purposes and based on different philosophical assumptions. They are designed to be enabling rather than prescriptive, and to make case study evaluation reporting on context and complex health interventions more comprehensive, accessible and useable.

Throat and voice problems in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

A small number of case reports and observational studies describe chronic nasal congestion, upper airway obstruction, dysphonia, vocal cord abnormalities, and swallowing abnormalities in the Ehlers-Danlos syndromes. Little is known of the causes and therefore treatments of these, yet they are not uncommon findings in persons with hypermobility-related conditions presenting in the healthcare setting. We have a specialist multidisciplinary ear, nose, and throat and speech therapy practice with accumulating observational and empirical experience of managing these conditions, which include altered voice, choking, high dysphagia and anterior and deep neck pains. Here, we present our experience, some illustrative cases, and suggestions for future work in this evolving field.

Rhetoric and Reality: User Engagement and Health Care Reform in England.

Policy discourse and rhetoric that preceded the Health and Social Care Act (HSCA) 2012 suggests the Act was intended to further embed issues relating to accountability, transparency, and engagement with service-users. Close analysis suggests economic imperatives and independent expert authority are promoted to a greater extent than previous reforms, while stakeholder engagement and accountability appear weakened in crucial areas. To show this, the article considers two important and underexplored activities under the HSCA: reporting and other types of stakeholder engagement measures. These two activities are important because they support the way crucial NHS functions are carried out. The article contends that the policy discourse and rhetoric underpinning these activities does not reflect the statutory reality.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19-89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αß T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αß/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sézary Syndrome.

Chemotherapy-induced peripheral neuropathy (CIPN) is common, frequently limits chemotherapy dosing, and negatively impacts quality of life. The National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0, and the Total Neuropathy Score clinical version (TNSc) are both validated scores to quantify peripheral neuropathy (PN), with the TNSc being more sensitive to clinical changes. Mycosis fungoides and Sézary syndrome (MF/SS) are characterized by a chronic course, where current therapies are generally non-curative and treatment toxicities have the potential for significant lasting effects. Brentuximab vedotin (BV) is an antibody-drug-conjugate composed of an anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent, monomethyl auristatin E, with a known associated CIPN. In our phase II clinical trial of BV in MF/SS, 25 (69%) of 36 patients developed PN, with 18 (50%) developing Clinically Significant PN, CTCAE v4.0 grade 2 or higher. The median time to grade 2 PN was 15 weeks (range 0.4-48) after the initial dose. By Kaplan-Meier calculation, the median time to improvement from Clinically Significant PN was 30 weeks from the last BV dose. Seventy-four percent had improvement by 24 months. We found that TNSc scores significantly correlated with CTCAE grade, with Spearman correlation coefficient 0.68 (p < 0.001). By logistic regression, for each 100 mg increase in BV total dose, the likelihood of developing Clinically Significant PN increased by 23% (95% CI 4-46%). Improved monitoring of CIPN associated with BV is of paramount importance in the MF/SS population.

c-CBL E3 Ubiquitin Ligase Expression Increases Across the Spectrum of Benign and Malignant T-Cell Skin Diseases.

Prolonged survival of lesional T cells plays a central role in the pathogenesis of T-cell-mediated dermatoses. We have recently shown that the ubiquitin ligase c-CBL is highly expressed in cutaneous T-cell lymphoma (CTCL) and that its knockdown increases activation-induced cell death, a key pathway for T-cell apoptosis. Here, we extend our work on c-CBL expression in malignant T cells to their nonneoplastic counterparts in benign inflammatory dermatoses. Immunohistochemical staining with anti-c-CBL antibody was performed on lesional biopsies from a total of 65 patients with atopic dermatitis, allergic contact dermatitis, pityriasis rosea, psoriasis vulgaris, lichen planus, mycosis fungoides (MF)/Sézary syndrome (SS) as well as on tonsil tissue from 5 individuals and on 5 human CTCL cell lines. Protein levels were measured in situ using multispectral image analysis, a quantitative method that is ×5 more sensitive than standard immunohistology for antigen detection. There was a significant (P < 0.05) and progressive increase of mean c-CBL expression across the spectrum of inflammatory dermatoses (2-fold), MF/SS (3-fold), and lymphoma cell lines (4-fold) as compared with tonsillar T lymphocytes. A subset of MF/SS cases expressed mean c-CBL levels above the ranges observed in inflammatory dermatoses. Given our prior finding that c-CBL inhibits activation-induced cell death, c-CBL might play a role in the pathogenesis of inflammatory dermatoses and CTCL.

Multiple Adult Xanthogranulomas Associated With Cutaneous Lymphoid Hyperplasia and Lupus Erythematosus.

A 50-year-old woman presented to our clinic for evaluation of numerous recurrent, pruritic papules on her upper extremities. She reported a 2- to 3-year history of up to eight unique lesions on the bilateral upper arms that would initially appear as firm papules before gradually softening and flattening out, leaving residual pink macules (Figure 1A). Her medical history was notable for mild hyperlipidemia. On presentation, she had several erythematous papules with overlying telangiectasias scattered throughout her bilateral upper arms. One lesion of concern over the left deltoid had been present for 5 months without signs of regression (Figure 1B). Pathology of this and a similar lesion showed histiocytes forming Touton giant cells with foamy cytoplasm consistent with a xanthogranuloma (AXG). Results from immunoperoxidase stains were negative for factor XIIIa and CD1a, diffusely positive for CD68, and focally positive for S100 (Figure 2).

Drug-induced pseudo-Sezary syndrome: a case report and literature review.

Pseudo-Sezary syndrome is a benign lymphoproliferative disorder, which clinically and pathologically mimics true Sezary syndrome. In this article, a case of pseudo-Sezary syndrome and review the literature has been reported. The patient was a 51-year-old man who developed erythroderma and palmoplantar keratoderma. The patient's medication history included fosinopril and combination metoprolol/hydrochlorothiazide. Flow cytometry showed a population of 2500 "Sezary-like" CD4726 T cells per microliter in the peripheral blood. Skin biopsy showed numerous atypical lymphocytes with epidermotropism, and there was matching dominant T-cell clonality in the skin and peripheral blood. After stopping all antihypertensive medications, the eruption resolved in its entirety.

Multispectral Imaging Approach to the Diagnosis of a CD20+ Cutaneous T-cell Lymphoproliferative Disorder: A Case Report.

Expression of the pan B-cell marker CD20 by T-cell lymphoproliferative disorders is exceedingly rare. We present a 52-year-old man with a unilesional cutaneous CD20 T-cell lymphoproliferative disorder. Multispectral imaging analysis of CD3-CD20 double-stained lesional tissue sections allowed (1) the visualization of double-positive T lymphocytes in situ with sensitivity superior to that of conventional immunohistochemistry and (2) the quantitative assessment of marker coexpression. Here, 23% of CD3 signals in the patient's lesion were also CD20, whereas 38% of CD20 signals were also CD3. In contrast, both parameters were below 1% in the tonsil control. Overall, the percentage of double-positive cells in lesional skin was 35%, although only 0.4% of such cells were detected in the tonsil. This is the first demonstration of aberrant CD20 expression by skin-infiltrating T cells using multispectral imaging.

Prodifferentiation, anti-inflammatory and antiproliferative effects of delphinidin, a dietary anthocyanidin, in a full-thickness three-dimensional reconstituted human skin model of psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disorder of skin and joints for which conventional treatments that are effective in clearing the moderate-to-severe disease are limited due to long-term safety issues. This necessitates exploring the usefulness of botanical agents for treating psoriasis. We previously showed that delphinidin, a diet-derived anthocyanidin endowed with antioxidant and anti-inflammatory properties, induces normal epidermal keratinocyte differentiation and suggested its possible usefulness for the treatment of psoriasis [1]. OBJECTIVES: To investigate the effect of delphinidin (0-20 µM; 2-5 days) on psoriatic epidermal keratinocyte differentiation, proliferation and inflammation using a three-dimensional reconstructed human psoriatic skin equivalent (PSE) model. METHODS: PSEs and normal skin equivalents (NSEs) established on fibroblast-contracted collagen gels with respective psoriatic and normal keratinocytes and treated with/without delphinidin were analyzed for histology, expression of markers of differentiation, proliferation and inflammation using histomorphometry, immunoblotting, immunochemistry, qPCR and cultured supernatants for cytokine with a Multi-Analyte ELISArray Kit. RESULTS: Our data show that treatment of PSE with delphinidin induced (1) cornification without affecting apoptosis and (2) the mRNA and protein expression of markers of differentiation (caspase-14, filaggrin, loricrin, involucrin). It also decreased the expression of markers of proliferation (Ki67 and proliferating cell nuclear antigen) and inflammation (inducible nitric oxide synthase and antimicrobial peptides S100A7-psoriasin and S100A15-koebnerisin, which are often induced in psoriatic skin). ELISArray showed increased release of psoriasis-associated keratinocyte-derived proinflammatory cytokines in supernatants of the PSE cultures, and this increase was significantly suppressed by delphinidin. CONCLUSIONS: These observations provide a rationale for developing delphinidin for the management of psoriasis.

Quantitative gene analysis of methylation and expression (Q-GAME) in fresh or fixed cells and tissues.

Epigenetic regulation of gene expression by DNA methylation is a central mechanism governing the silencing of tumor suppressor genes in many forms of cancer. Current methods have not proven optimal for the quantitative analysis of DNA methylation and corresponding in situ protein expression within cells in small specimens like skin biopsies. We have overcome this limitation by combining and modifying several techniques: target cell enrichment, DNA micro-isolation, one-step denaturation/bisulphite conversion/in-column desulphonation, specially designed PCR amplification, pyrosequencing and multispectral image analysis. Using this approach optimized for small samples, we can quantify minor alterations in gene methylation and protein expression using minimal amounts of tissue. Comparative studies of fresh and processed cells showed that our method is valid for DNA in both fresh and formalin-fixed, paraffin-embedded specimens. We can measure the effects of DNA methylation inhibitors, administered in vitro or in vivo, on the promoter methylation and protein expression of selected genes in specific cells. This novel approach should prove useful for a wide variety of investigative and clinical applications in dermatology and other specialties where the collection of small, routinely processed biopsy specimens is common. We refer to this method as Q-GAME (quantitative gene analysis of methylation and expression).

Methotrexate inhibits the viability of human melanoma cell lines and enhances Fas/Fas-ligand expression, apoptosis and response to interferon-alpha: rationale for its use in combination therapy.

Melanoma, a highly aggressive form of cancer, is notoriously resistant to available therapies. Methotrexate (MTX), an antifolate, competitively inhibits DNA synthesis and is effective for several types of cancer. In cutaneous T-cell lymphoma (CTCL), MTX increases Fas death receptor by decreasing Fas promoter methylation by blocking the synthesis of SAM, the principal methyl donor for DNMTs, resulting in enhanced Fas-mediated apoptosis. The objective of this study was to explore the effects of MTX in human melanoma. MTX variably inhibited the survival of melanoma cells and induced apoptosis as evident by annexin V positivity and senescence associated ß-galactosidase activity induction. Furthermore, MTX caused increased transcript and protein levels of extrinsic apoptotic pathway factors Fas and Fas-ligand, albeit at different levels in different cell lines. Our pyrosequencing studies showed that this increased expression of Fas was associated with Fas promoter demethylation. Overall, the ability of MTX to up-regulate Fas/FasL and enhance melanoma apoptosis through extrinsic as well as intrinsic pathways might make it a useful component of novel combination therapies designed to affect multiple melanoma targets simultaneously. In support of this concept, combination therapy with MTX and interferon-alpha (IFNα) induced significantly greater apoptosis in the aggressive A375 cell line than either agent alone.

Non-melanoma skin cancer event rates in a formalized clinical trial setting: considerations for clinical trial design.

BACKGROUND: Here we report clinical risk factors and event rates for the development of new non-melanoma skin cancer (NMSC) in a randomized, double-blind, placebo-controlled trial of the irreversible ornithine decarboxylase (ODC) inhibitor, difluromethylornithine (DFMO), over a 3-5-year follow-up. METHODS: 147 placebo patients (white; mean age 60.2 years; 60% male) were evaluated for event rates and association of initial skin biomarkers and baseline patient characteristics with the development of squamous cell (SCC) and basal cell (BCC) carcinomas. RESULTS: Post-study evaluation (median follow-up 4.4 years) indicates the measures of prior NMSCs ( P  ≤ 0.001), prior BCCs ( P  ≤ 0.001), prior SCCs ( P  = 0.011), prior tumor rate ( P  = 0.002), hemoglobin ( P  = 0.022), and gender ( P  = 0.045) as significant predictors for new NMSC development. Similarly, all measures of prior BCCs and NMSCs ( P  < 0.001), prior tumor rate ( P  = 0.014), and SCCs in the prior 2 years ( P  = 0.047) were statistically significant predictors for new BCC development. Total prior NMSCs and those in the prior 5 years ( P  < 0.001), total prior SCCs and those in the prior 5 years ( P  < 0.001), total prior BCCs and those in the prior 5 years ( P  ≤ 0.001), prior tumor rate ( P  = 0.011) as well as age ( P  = 0.008), hemoglobin ( P  = 0.002), and gender ( P  = 0.003) were statistically significant predictors of new SCC development. TPA-induced ODC activity at baseline showed no statistically significant association with the development of new NMSC ( P  = 0.35), new BCCs ( P  = 0.62), or new SCCs ( P  = 0.25). CONCLUSION: In the studied population, the history of and rate at which prior NMSCs occur are predictive and should be controlled for in future NMSC prevention trials.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Delphinidin, a dietary antioxidant, induces human epidermal keratinocyte differentiation but not apoptosis: studies in submerged and three-dimensional epidermal equivalent models.

Delphinidin (Del), [3,5,7,3'-,4'-,5'-hexahydroxyflavylium], an anthocyanidin and a potent antioxidant abundantly found in pigmented fruits and vegetables exhibits proapoptotic effects in many cancer cells. Here, we determined the effect of Del on growth, apoptosis and differentiation of normal human epidermal keratinocytes (NHEKs) in vitro in submerged cultures and examined its effects in a three-dimensional (3D) epidermal equivalent (EE) model that permits complete differentiation reminiscent of in vivo skin. Treatment of NHEKs with Del (10-40 µm; 24-48 h) significantly enhanced keratinocyte differentiation. In Del-treated cells, there was marked increase in human involucrin (hINV) promoter activity with simultaneous increase in the mRNA and protein expressions of involucrin and other epidermal differentiation markers including procaspase-14 and transglutaminase-1 (TGM1), but without any effect on TGM2. Del treatment of NHEKs was associated with minimal decrease in cell viability, which was not associated with apoptosis as evident by lack of modulation of caspases, apoptosis-related proteins including Bcl-2 family of proteins and poly(ADP-ribose) polymerase cleavage. To establish the in vivo relevance of our observations in submerged cultures, we then validated these effects in a 3D EE model, where Del was found to significantly enhance cornification and increase the protein expression of cornification markers including caspase-14 and keratin 1. For the first time, we show that Del induces epidermal differentiation using an experimental system that closely mimics in vivo human skin. These observations suggest that Del could be a useful agent for dermatoses associated with epidermal barrier defects including aberrant keratinization, hyperproliferation or inflammation observed in skin diseases like psoriasis and ichthyoses.

The optimal timing of forensic evidence collection following paediatric sexual assault.

BACKGROUND: Forensic evidence collection following sexual assault has an important medico-legal role. Despite the advent of DNA profiling, research into the optimisation of forensic biological specimen collection is limited. This has led to inconsistent and variable guidelines for forensic evidence collection. The guidelines in this jurisdiction (Victoria, Australia) recommends that specimens be collected up to 7 days following sexual assault in some circumstances. The aims of this study were to determine the optimal times post sexual assault for the collection of forensic biological evidence in paediatric cases (aged 0-17 years). METHODS: A retrospective review of paediatric sexual assault cases seen by the Victorian Forensic Paediatric Medical Service (VFPMS) between 1 January 2009, and 1 May 2016, was undertaken. Specimen site and collection times post assault were collated from VFPMS medico-legal reports and compared with the forensic evidence analysis results reported by the Victoria Police, Forensic Services Department. In addition, a survey of recommended forensic specimen collection times post assault in the different Australian jurisdictions was undertaken for comparison. RESULTS: Within the 6 year 5 month period studied there were 122 cases consisting of 562 different forensic specimens that were collected and analysed. 62 (51%) of cases produced one or more positive forensic result and, of the 562 specimens collected, 153 (27%) were positive for one or more of foreign DNA, spermatozoa, semen or saliva. Foreign DNA was more likely to be found if forensic specimens were collected during the first 24 h after the assault as compared with those collected at 25-48 h, (p < 0.005). Similarly, spermatozoa were identified more frequently on swabs collected at 0-24 h compared to 25-48 h (p < 0.002). Foreign DNA was not identified beyond 48 h post assault and spermatozoa were not identified beyond 36 h. Saliva and semen were not identified beyond 24 h. The youngest victims with positive forensic evidence were 2-3 years old. The survey of current forensic specimen collection practice in Australia shows that the guidelines for timing of forensic evidence collection in child sexual assault cases is highly variable between jurisdictions. CONCLUSIONS: Our results highlight the importance of collecting forensic specimens as a matter of urgency, regardless of age, within the first 48 h post assault. Although there is need for further research, the findings indicate a need for the re-evaluation of current guidelines for specimen collection in paediatric sexual assault cases.

Self-reported throat symptoms in Ehlers-Danlos syndromes and hypermobility spectrum disorders: A cross-sectional survey study.

Objectives: This study identified the frequency and severity of dysphagia, dysphonia, and laryngopharyngeal reflux symptoms in people with Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD) and explored differences between diagnostic groups. Methods: Participants were recruited via non-probability convenience sampling. Information was gathered via online survey, including the Reflux Symptom Index (RSI; Belafsky et al., J Voice. 2002;16:274-277), the Eating and Drinking Assessment Tool (EAT-10; Belafsky et al., Ann Otol Rhinol Laryngol. 2008;117:919-924), and the Voice Handicap Index (VHI; Jacobson et al., Am J Speech Lang Pathol. 1997;6(3):66-70). These were analyzed using ANOVAs. Results: There were 1620 participants (96.6% female, 2.8% male) that met the inclusion criteria. The mean age was 38.09 (SD 12.22). 75.51% had hypermobile EDS (hEDS), 17.83% had HSD and 3.33% had classic EDS (cED). The cohort's mean scores were RSI = 22.95 (SD 9.01), EAT-10 = 11.91 (SD 9.66), and VHI score = 31.99 (SD 24.36). The hEDS group had significantly higher mean scores than the HSD group on RSI score and on some RSI items, on EAT-10 score and on all EAT-10 items, and on one VHI item. Conclusion: People with EDS/HSD experience symptoms of acid reflux, dysphagia, and dysphonia to varying degrees with significant differences between hEDS than HSD. Awareness of the impact of EDS/HSD on throat symptoms will enable health care professionals to anticipate throat symptoms more readily in this population, providing individualized and effective management plans. Level of Evidence: IV.

Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise.

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy.