Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis

Abstract

Background/Objectives

Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability.

Methods

In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY).

Results

Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability.

Conclusions

Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.

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An original procedure for orbitonasal cutaneous infiltrative tumor repair, using combined forehead and melolabial propeller flaps

Abstract

Introduction

Resections of cutaneous tumors in the medial orbitonasal region can be transfixing. Repairs using a single local flap run the risk of failure and that of secondary sinonasal fistula, especially in cases of surgery on a radiated field. We propose an original and reliable repair procedure using two pedicled regional flaps vascularized by two distinct arterial systems clinched together to reconstruct the mucosal and cutaneous planes.

Materials and methods

A first melolabial propeller flap (MPF) with a superior perforating pedicle was elevated and the cutaneous side was sutured to the deep plane of the loss of substance (mucosal lining). A second homolateral or contralateral paramedian forehead flap (PFF) was then lifted and sutured over the first flap (superficial plane). The forehead pedicle flap was divided at 1 month.

Results

No trophic complication or failure was recorded on two patients. The 7-year carcinologic, aesthetic, and functional results were satisfying.

Conclusion

This technique involving the superimposition of two local flaps, vascularized by two different arterial systems, appears to offer a simple and reliable repair technique for transfixing cutaneous losses of substance in the medial orbitonasal region. It could be used in the first-line treatment, particularly if an additional radiotherapy is to be performed.

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IL‐27 Signaling Deficiency Develops Th17‐enhanced Th2‐dominant Inflammation in Murine Allergic Conjunctivitis Model

Abstract

Background

While most studies focus on pro‐allergic cytokines, the protective role of immunosuppressive cytokines in allergic inflammation is not well elucidated. This study was to explore a novel anti‐inflammatory role and cellular/molecular mechanism of IL‐27 in allergic inflammation.

Methods

A murine model of experimental allergic conjunctivitis (EAC) was induced in BALB/c, C57BL/6 or IL‐27Rα deficient (WSX‐1 ^‐/‐) mice by short ragweed pollen, with untreated or PBS‐treated mice as controls. The serum, eyeballs, conjunctiva, cervical lymph nodes (CLNs) were used for study. Gene expression was determined by RT‐qPCR, protein production and activation were evaluated by immunostaining, ELISA and Western blotting.

Results

Typical allergic manifestations and stimulated TSLP signaling and Th2 responses were observed in ocular surface of EAC models in BALB/c and C57BL/6 mice. The decrease of IL‐27 at mRNA (IL‐27/EBI3) and protein levels were detected in serum, conjunctiva and CLN, as evaluated by RT‐qPCR, immunofluorescent staining, ELISA and Western blotting. EAC induced in WSX‐1 ^‐/‐ mice showed aggravated allergic signs with higher TSLP‐driven Th2‐dominant inflammation, accompanied by stimulated Th17 responses, including IL‐17A, IL‐17F, and transcription factor RORγt. In contrast, Th1 cytokine IFNγ and Treg marker IL‐10, with their respective transcription factors T‐bet and foxp3 were largely suppressed. Interestingly, imbalanced activation between reduced phosphor (P)‐STAT1 and stimulated P‐STAT6 were revealed in EAC, especially WSX‐1 ^‐/‐ ‐EAC mice.

Conclusion

These findings demonstrated a natural protective mechanism by IL‐27, of which signaling deficiency develops a Th17‐type hyper‐response that further aggravates Th2‐dominant Allergic Inflammation.

This article is protected by copyright. All rights reserved.

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Emerging concepts and challenges in implementing the exposome paradigm in allergic diseases and asthma

Abstract

Exposome research can improve the understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the lifespan. The exposomic approach provides a risk profile instead of single predictors and thus is particularly applicable to allergic diseases and asthma. Under the PRACTALL collaboration between the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma and Immunology (AAAAI) we evaluated the current concepts and the unmet needs on the role of the exposome in allergic diseases and asthma.

This article is protected by copyright. All rights reserved.

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Ertapenem – a potent treatment for clinical and quality of life improvement in patients with hidradenitis suppurativa— Reply

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Thick nails, plantar keratoderma, follicular hyperkeratosis, and leukokeratosis associated with a novel mutation in KRT6A gene

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Soft tissue reactions following cochlear implantation

Abstract

Introduction

Cochlear implantation is a boon to children with hearing loss. Rarely, it can be associated with complications. Soft tissue reaction can be a particularly distressing complication.

Materials and methods

The study was conducted on all patients presenting with soft tissue reaction post-cochlear implant in a tertiary care referral institute from March 2011 to June 2018. We graded the severity of soft tissue reaction as per the severity and then managed these patients accordingly.

Results

Thirty-five patients were included in this study. Grade 1 had 12 patients, grade 2 had 9, grade 3 had 4 and grade 4 had 9 patients. Grade 1, 2 and 3 reactions were managed conservatively, while grade 4 required surgery. The incidence of explantations increased with the grade severity.

Conclusion

Soft tissue reaction post-cochlear implant is a rare, but distressing complication. Grading and analyzing them can help us manage them in a better way.

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