Midfacial toddler excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders: midfacial toddler excoriation syndrome (MiTES; itch with normal pain sensation associated with 18 homozygous alanines (18A); and congenital insensitivity to pain (CIP) with normal itch associated with 19 homozygous alanines (19A). Knowledge of the phenotype, genotype and disease mechanism of MiTES is incomplete. Why 18A vs. 19A PRDM12 can cause almost opposite phenotypes is unknown; no other polyalanine or polyglutamine tract expansion disease causes two such disparate phenotypes. OBJECTIVES: To assess the genotype and phenotype of nine new, nine atypical and six previously reported patients diagnosed with MiTES. METHODS: Using cell lines with homozygous PR domain zinc finger protein 12 (PRDM12) containing 12 alanines (12A; normal), 18A (MiTES) and 19A (CIP), we examined PRDM12 aggregation and subcellular localization by image-separation confocal microscopy and subcellular fractionation Western blotting. RESULTS: MiTES presents in the first year of life; in all cases the condition regresses over the first decade, leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12 CIP are rarely found. The genotype-phenotype study of the PRDM12 polyalanine tract shows that having 7-15 alanines is normal; 16-18 alanines is associated with MiTES; 19 alanines leads to CIP; and no clinically atypical cases of MiTES had a polyalanine tract expansion. PRDM12 aggregation and subcellular localization differed significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein-aggregation disease. CONCLUSIONS: We provide diagnostic criteria for MiTES and improved longitudinal data. MiTES and CIP are distinct phenotypes, despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells. We hypothesize that the developmental environment of the trigeminal ganglion is unique and critically sensitive to pre- and postnatal levels of PRDM12.

Midfacial toddler excoriation syndrome (MiTES) causes facial itching and scratching in babies during their first year of life. MiTES tends to improve over the time period of approximately 10 years, but it can leave scars. Congenital insensitivity to pain (CIP) is a condition where a person cannot feel pain and is present from birth. This study looked at two conditions: MiTES and CIP. We specifically investigated changes in a gene called PRDM12, focusing on a part of the gene called the polyalanine tract ­ a sequence of many alanines (alanine is a type of amino acid). We discovered that the normal range for this sequence is between 7 and 15 alanines. If there are 16 to 18 alanines, it is associated with MiTES and causes the PRDM12 protein to clump together inside the cell. However, if there are 19 alanines, it leads to CIP, and the PRDM12 protein clumps together and moves to the cytoplasm, where it should not be. We found new evidence to suggest that MiTES is a disease where proteins clump together. Overall, our study findings show that despite there only being a small change in the same gene, MiTES and CIP are very different conditions.

Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial.

BACKGROUND: Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings. OBJECTIVES: To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial. METHODS: We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2-16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg-1 daily) or MTX (0.4 mg kg-1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status. RESULTS: In total, 103 participants were randomized (May 2016-February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD -5.69, 97.5% confidence interval (CI) -10.81 to -0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23-5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13-0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42-6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE. CONCLUSIONS: Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.

Getting it right the first time: an Irish paediatric dermatology perspective from a national care centre.

The Dermatology: 'Getting It Right the First Time' (GIRFT) Programme National Specialty Report recommended improving access to, and the quality of, paediatric dermatology services. Understanding referral patterns makes it easier to identify areas that can be improved. This study analysed 292 new referrals to a national care centre that provides secondary care to 50% of all Irish children. Results showed that 51% of new referrals could have been managed in primary care and 41% of new referrals were inappropriate, including 5.5% having no abnormal skin findings. These results indicate that up to 876 referrals could have been avoided over a 13-month period, freeing up resources and reducing wait times for cases more appropriate for a secondary and tertiary care centre. This would improve access for children, allowing them to be diagnosed at the right place and time, in alignment with GIRFT values.

Dermatitis in an irritable infant.

This is the case of an infant with a persistent dermatitis affecting the perioral, acral and napkin areas, in whom a simple oral therapy provided a rapid treatment response.

Review of applications of high-throughput sequencing in personalized medicine: barriers and facilitators of future progress in research and clinical application.

There has been an exponential growth in the performance and output of sequencing technologies (omics data) with full genome sequencing now producing gigabases of reads on a daily basis. These data may hold the promise of personalized medicine, leading to routinely available sequencing tests that can guide patient treatment decisions. In the era of high-throughput sequencing (HTS), computational considerations, data governance and clinical translation are the greatest rate-limiting steps. To ensure that the analysis, management and interpretation of such extensive omics data is exploited to its full potential, key factors, including sample sourcing, technology selection and computational expertise and resources, need to be considered, leading to an integrated set of high-performance tools and systems. This article provides an up-to-date overview of the evolution of HTS and the accompanying tools, infrastructure and data management approaches that are emerging in this space, which, if used within in a multidisciplinary context, may ultimately facilitate the development of personalized medicine.

Catalogue of inherited disorders found among the Irish Traveller population.

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.

Integrated metagenomic analysis of the rumen microbiome of cattle reveals key biological mechanisms associated with methane traits.

Methane is one of the major contributors to global warming. The rumen microbiota is directly involved in methane production in cattle. The link between variation in rumen microbial communities and host genetics has important applications and implications in bioscience. Having the potential to reveal the full extent of microbial gene diversity and complex microbial interactions, integrated metagenomics and network analysis holds great promise in this endeavour. This study investigates the rumen microbial community in cattle through the integration of metagenomic and network-based approaches. Based on the relative abundance of 1570 microbial genes identified in a metagenomics analysis, the co-abundance network was constructed and functional modules of microbial genes were identified. One of the main contributions is to develop a random matrix theory-based approach to automatically determining the correlation threshold used to construct the co-abundance network. The resulting network, consisting of 549 microbial genes and 3349 connections, exhibits a clear modular structure with certain trait-specific genes highly over-represented in modules. More specifically, all the 20 genes previously identified to be associated with methane emissions are found in a module (hypergeometric test, p<10-11). One third of genes are involved in methane metabolism pathways. The further examination of abundance profiles across 8 samples of genes highlights that the revealed pattern of metagenomics abundance has a strong association with methane emissions. Furthermore, the module is significantly enriched with microbial genes encoding enzymes that are directly involved in methanogenesis (hypergeometric test, p<10-9).

The role of fortified foods and nutritional supplements in increasing vitamin D intake in Irish preschool children.

PURPOSE: There are limited data on the contribution of fortified foods and nutritional supplements to intakes of vitamin D in young children. Our objective was to examine the intake, adequacy, risk of excessive intake and sources of dietary vitamin D. METHODS: The nationally representative cross-sectional dietary survey of young children (aged 1-4 years) (n 500) was used to evaluate vitamin D intake and quantify the contribution of the base diet, fortified foods and nutritional supplements to total intake. RESULTS: Median (IQR) intakes of vitamin D were generally low in this young population, ranging from 2.0 (1.9) to 2.5 (4.9) µg/day. Ninety-three and 78 % of children had intakes below 10 and 5 µg/day, respectively. While vitamin D supplement users (17 %) had the highest intakes [6.7 (6.4) µg/day] (P < 0.001), 74 % had intakes below 10 µg/day. Vitamin D-fortified foods, consumed by 77 % of children [2.2 (2.0) µg/day], made nutritionally significant contributions to intake [0.8 (1.6) µg/day], particularly in younger children [1.5 (4.6) µg/day]. Children who did not use nutritional supplements or fortified foods had significantly (P < 0.001) lower intakes of vitamin D than the other groups [1.0 (0.8) µg/day]. Our analyses show the importance of milk and yoghurt, meat and fortified ready-to-eat cereals as sources of vitamin D in this age group. The use of nutritional supplements or fortified foods at current levels does not represent a risk of intakes exceeding the European Food Safety Authority (EFSA) tolerable upper intake level (UL) (50 µg/day), as intakes did not exceed or even approach the UL (P95: 22 % of UL). CONCLUSION: Intakes of vitamin D in preschool children in Ireland are generally low. Nutritional supplements and fortified foods make significant contributions to intakes of vitamin D, without risk of unacceptably high intakes. Though supplements are effective in raising intakes of vitamin D in users, uptake is low (17 %). Food fortification may represent a suitable public health approach to increasing vitamin D intakes. The national food consumption data of Irish preschool children provide the ideal starting point for modelling of fortification scenarios to identify which foods and levels of addition will ensure effective and safe increases in vitamin D intake.

Hemosiderotic Juvenile Xanthogranuloma.

Juvenile xanthogranuloma is a non-Langerhans cell lesion mostly limited to the skin but occasionally presenting in extracutaneous locations or associated with systemic conditions. Lesions need to be distinguished mainly from dermatofibroma, xanthoma, Langerhans cell histiocytosis, or reticulohistiocytoma. Herein, we present a hemosiderotic variant of juvenile xanthogranuloma in a 12-year-old girl, which we have not found described in literature. The lesion presented at the back of the scalp as a slowly growing yellowish polypoid lesion showing occasional bleeding. The histopathological examination demonstrated a cellular infiltrate expanding the dermis, with a Grenz zone and with no remarkable changes in the overlying epidermis. The papule was made of mononucleated macrophages, many of which were xanthomatous. There were some Touton giant cells. The lesion was intermingled with a mild inflammatory infiltrate comprising lymphocytes, plasma cells, neutrophils, and some eosinophils. Many of the macrophages contained abundant cytoplasmic deposits of iron. The macrophages expressed CD68 and CD163, whereas they failed to express S100 protein, CD1a, and Langerin.

A computational framework for the prioritization of disease-gene candidates.

BACKGROUND: The identification of genes and uncovering the role they play in diseases is an important and complex challenge. Genome-wide linkage and association studies have made advancements in identifying genetic variants that underpin human disease. An important challenge now is to identify meaningful disease-associated genes from a long list of candidate genes implicated by these analyses. The application of gene prioritization can enhance our understanding of disease mechanisms and aid in the discovery of drug targets. The integration of protein-protein interaction networks along with disease datasets and contextual information is an important tool in unraveling the molecular basis of diseases. RESULTS: In this paper we propose a computational pipeline for the prioritization of disease-gene candidates. Diverse heterogeneous data including: gene-expression, protein-protein interaction network, ontology-based similarity and topological measures and tissue-specific are integrated. The pipeline was applied to prioritize Alzheimer's Disease (AD) genes, whereby a list of 32 prioritized genes was generated. This approach correctly identified key AD susceptible genes: PSEN1 and TRAF1. Biological process enrichment analysis revealed the prioritized genes are modulated in AD pathogenesis including: regulation of neurogenesis and generation of neurons. Relatively high predictive performance (AUC: 0.70) was observed when classifying AD and normal gene expression profiles from individuals using leave-one-out cross validation. CONCLUSIONS: This work provides a foundation for future investigation of diverse heterogeneous data integration for disease-gene prioritization.

Use of a novel laparoscopic gastrostomy technique in children with severe epidermolysis bullosa.

OBJECTIVE: Supplementing nutrition in children with severe epidermolysis bullosa (EB) is challenging because of skin and mucosal fragility. Percutaneous endoscopic gastrostomy is contraindicated in EB, whereas more invasive open surgical gastrostomy placement can be complicated by chronic leakage. The aim of the study was to review the efficacy and acceptability, in children with severe EB, of our modified 2-port laparoscopic approach using the Seldinger technique with serial dilatation and tube insertion through a peel-away sheath. METHODS: Retrospective review of children with EB who underwent laparoscopic feeding gastrostomy at our centre since 2009. RESULTS: Seven children (6 severe generalised recessive dystrophic EB, 1 non-Herlitz junctional EB; 2 girls, 5 boys) underwent modified laparoscopic gastrostomy placement at median age 4.85 years (range 1.0-8.8), with fundoplication for gastro-oesophageal reflux in 1 case, with follow-up for 0.3 to 3.9 years. The procedure was well tolerated with oral feeds usually given after 4 hours and whole protein gastrostomy feeds within 24 hours in 6 patients. Improved growth was reflected in mean weight and height z scores: -1.36 (range -2.6 to 0.5) to -0.61 (range -2.34 to 2.0) and -1.09 (range -2.42 to 1.0) to 0.71 (range -1.86 to 1.0), respectively. Postoperatively, 5 patients experienced minor local complications: minimal leakage without skin damage in 3 and transient peristomal granulation rapidly responsive to topical treatment in 2; this followed acute gastrostomy site infection in 1. There was no leakage after the immediate postoperative period. CONCLUSIONS: We conclude that our less-invasive laparoscopic gastrostomy technique is effective and better tolerated in children with severe EB, at least in the medium term, than open gastrostomy placement. Longer follow-up is required.

Serum 25-hydroxyvitamin D levels in patients with atopic eczema and the influence of narrowband ultraviolet B phototherapy.

BACKGROUND: Narrowband ultraviolet B phototherapy (nbUVB) is an established treatment modality for patients with severe atopic dermatitis (AD) and is known to increase serum vitamin D levels (SVD). The relationship between SVD and AD remains unclear. OBJECTIVES: To assess SVD and disease severity in patients with AD before and after nbUVB and establish whether a change in SVD correlates to response to nbUVB. Methods: A single-centre, open observational study recruited 21 male and 17 female patients with AD between November and April. Eczema severity was measured using the SCORAD tool, and serum 25-hydroxyvitamin D3 levels were determined before and after nbUVB, which was administered thrice weekly. RESULTS: Nine patients had severe AD, 23 moderate and six mild, as indicated by SCORAD measurements. Seventeen patients completed the study. Median SVD increased from 45 nmol/l pre-treatment to 169 nmol/l post-treatment (95% CI 2.9­5.0 times baseline) (P < 0.0001). Mean SCORAD reduction following nbUVB was significant at 21.9 units (95% CI, 14.9­28.9) (P < 0.0001). No evidence of a relationship between change in SCORAD and change in SVD was found. LIMITATIONS: A significant number of patients failed to complete the study. CONCLUSIONS: Patients with AD are at risk of vitamin D deficiency. Correlation between this and disease severity has been postulated, but this study does not provide confirmatory evidence.

Multiple cerebral abscesses in Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome is characterised by palmoplantar keratoderma, periodontitis and pyogenic infections. We describe the first case of brain abscess in a child with this syndrome. We highlight the importance of recognising any associated diagnosis, however rare or apparently irrelevant, in an acutely and critically ill child.

Novel mixed-method, inclusive protocol involving global key stakeholders, including carers as experts, to co-develop relevant Caregiver-Reported Outcome Domains (CRODs) in skin disease.

INTRODUCTION: Ichthyoses comprise a heterogenous group of rare genetic skin disorders that involves the entire skin surface, often with additional syndromic features, and pose many clinical challenges. Without curative intervention, the mainstay of life-long symptom management is supportive in nature and can remain the responsibility of the caregiver. Although impact on the wider family is considered an important outcome of policies and services, there is a lack of caregiver consensus on what outcome domains to measure to fully assess the impact of ichthyosis on the patient and the caregiver. This project aims to identify a set of core outcome domains towards a core outcome set for ichthyosis that can measure all relevant concepts of ichthyosis in clinical practice, service delivery and research. METHODS AND ANALYSIS: Following the COMET (Core Outcome Measures in Effectiveness Trials) initiative, this project will employ a mixed-method study design which was developed using public and patient involvement and an international multidisciplinary expert group (clinical experts, patients and their representatives, policymakers, researchers and service providers). Experts by experience, or caregivers, will be recruited through online ichthyosis support groups. Phase one will focus on item generation and involve: (1) a systematic literature review, (2) a multimethods international qualitative study with ichthyosis caregivers and (3) co-development of items for an e-survey. Phase two, item refinement, will employ a novel four-pronged consensus approach: (1) an e-Delphi survey, (2) statistical analysis of e-Delphi survey results, (3) online qualitative feedback and (4) an online consensus discussion. All methodological considerations will be clearly linked with each Core Outcome Set-STAndards for Developing recommendation. ETHICS AND DISSEMINATION: Research Ethics Committee approval obtained from the School of Psychology, Ulster University (UK)(Ref:REC/20/0004). Results will be presented in published international peer-reviewed journals, at scientific meetings and support groups. REGISTRATION: COMET database (January 2019).

Psoralen and ultraviolet A in the treatment of granuloma annulare.

BACKGROUND: Granuloma annulare (GA) is a benign, usually self-limiting disease. Lesions may be localized or generalized with a tendency for generalized disease to follow a chronic course. There is evidence to support psoralen and ultraviolet A (PUVA) in the treatment of GA, but little data on long-term benefits. The purpose of this study was to investigate the effect of PUVA in the treatment of GA, and to establish clearance and remission rates. METHODS: We carried out a retrospective study of patients with generalized GA treated with PUVA over 13 years. Data were collected from case notes and a phototherapy database. On completion of treatment, outcome was assessed as clear, good improvement, moderate improvement and poor outcome. Follow-up data were obtained for patients who had cleared using a postal questionnaire in addition to clinic notes. RESULTS: Fifty per cent of courses resulted in clearance of disease, 16% in good improvement, 25% had moderate benefit and 9% had a poor outcome. Of the patients that cleared, 79% remained in remission at 6 months but only 32% were still clear 12 months following treatment. CONCLUSION: Our findings show clearance or good improvement of generalized GA in 66% of cases. Prolonged remission, however, occurred in less than a third of patients.

Data mining and machine learning approaches for prediction modelling of schistosomiasis disease vectors: Epidemic disease prediction modelling.

This research presents viable solutions for prediction modelling of schistosomiasis disease based on vector density. Novel training models proposed in this work aim to address various aspects of interest in the artificial intelligence applications domain. Topics discussed include data imputation, semi-supervised labelling and synthetic instance simulation when using sparse training data. Innovative semi-supervised ensemble learning paradigms are proposed focusing on labelling threshold selection and stringency of classification confidence levels. A regression-correlation combination (RCC) data imputation method is also introduced for handling of partially complete training data. Results presented in this work show data imputation precision improvement over benchmark value replacement using proposed RCC on 70% of test cases. Proposed novel incremental transductive models such as ITSVM have provided interesting findings based on threshold constraints outperforming standard SVM application on 21% of test cases and can be applied with alternative environment-based epidemic disease domains. The proposed incremental transductive ensemble approach model enables the combination of complimentary algorithms to provide labelling for unlabelled vector density instances. Liberal (LTA) and strict training approaches provided varied results with LTA outperforming Stacking ensemble on 29.1% of test cases. Proposed novel synthetic minority over-sampling technique (SMOTE) equilibrium approach has yielded subtle classification performance increases which can be further interrogated to assess classification performance and efficiency relationships with synthetic instance generation.