Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

BACKGROUND: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007).

This is an updated guideline for the diagnosis and management of allergic and non-allergic rhinitis, first published in 2007. It was produced by the Standards of Care Committee of the British Society of Allergy and Clinical Immunology, using accredited methods. Allergic rhinitis is common and affects 10-15% of children and 26% of adults in the UK, it affects quality of life, school and work attendance, and is a risk factor for development of asthma. Allergic rhinitis is diagnosed by history and examination, supported by specific allergy tests. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. Combination therapy with intranasal corticosteroid plus intranasal antihistamine is more effective than either alone and provides second line treatment for those with rhinitis poorly controlled on monotherapy. Immunotherapy is highly effective when the specific allergen is the responsible driver for the symptoms. Treatment of rhinitis is associated with benefits for asthma. Non-allergic rhinitis also is a risk factor for the development of asthma and may be eosinophilic and steroid-responsive or neurogenic and non- inflammatory. Non-allergic rhinitis may be a presenting complaint for systemic disorders such as granulomatous or eosinophilic polyangiitis, and sarcoidoisis. Infective rhinitis can be caused by viruses, and less commonly by bacteria, fungi and protozoa.

Multifocal capillary malformations in an older, asymptomatic child with a novel RASA1 mutation.

Multifocal capillary malformation (CM) is the cardinal feature of patients with RASA1 mutations. These CMs are 'red flags', signalling the possible association with an arteriovenous malformation (AVM) or an arteriovenous fistula (AVF). We report an 8-year-old boy who presented with > 20 CMs, who was found to have a novel mutation in the RASA1 gene. Radiological screening of children with RASA1 mutations is not standardized, and we elected to carry out baseline magnetic resonance imaging of the brain and spine in our case, which gave normal results. We discuss the recent literature and our approach in the management of such a case.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

BSACI guideline for the management of chronic urticaria and angioedema.

This guidance for the management of patients with chronic urticaria and angioedema has been prepared by the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is aimed at both adult physicians and paediatricians practising in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a Web-based system. Their comments and suggestions were carefully considered by the Standards of Care Committee. Where evidence was lacking, a consensus was reached by the experts on the committee. Included in this management guideline are clinical classification, aetiology, diagnosis, investigations, treatment guidance with special sections on children with urticaria and the use of antihistamines in women who are pregnant or breastfeeding. Finally, we have made recommendations for potential areas of future research.

Management of allergy to penicillins and other beta-lactams.

The Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) and an expert panel have prepared this guidance for the management of immediate and non-immediate allergic reactions to penicillins and other beta-lactams. The guideline is intended for UK specialists in both adult and paediatric allergy and for other clinicians practising allergy in secondary and tertiary care. The recommendations are evidence based, but where evidence is lacking, the panel reached consensus. During the development of the guideline, all BSACI members were consulted using a Web-based process and all comments carefully considered. Included in the guideline are epidemiology of allergic reactions to beta-lactams, molecular structure, formulations available in the UK and a description of known beta-lactam antigenic determinants. Sections on the value and limitations of clinical history, skin testing and laboratory investigations for both penicillins and cephalosporins are included. Cross-reactivity between penicillins and cephalosporins is discussed in detail. Recommendations on oral provocation and desensitization procedures have been made. Guidance for beta-lactam allergy in children is given in a separate section. An algorithm to help the clinician in the diagnosis of patients with a history of penicillin allergy has also been included.

Narrowband ultraviolet B phototherapy in children with moderate-to-severe eczema: a comparative cohort study.

BACKGROUND: There is only retrospective evidence for the efficacy of narrowband ultraviolet B (NB-UVB) in children with eczema. OBJECTIVES: To measure the difference in means for objective scores [Six Area Six Sign Atopic Dermatitis score (SASSAD), percentage surface area] and quality-of-life scores, between patients treated with NB-UVB and unexposed cohorts at the end of treatment, and 3 and 6 months post-treatment. METHODS: Twenty-nine children aged 3-16 years for whom NB-UVB was indicated, were scored prospectively using SASSAD and percentage surface area involvement at baseline, at 12 weeks (end of treatment) and 3 and 6 months post-NB-UVB. Their scores were compared with those of unexposed children (n = 26) for whom NB-UVB phototherapy was indicated and offered, but who chose not to undertake treatment. RESULTS: There was a 61% reduction in mean SASSAD score in the NB-UVB cohort compared with an increase of 6% in the unexposed cohort. Mean SASSAD score for the NB-UVB cohort at the end of treatment was 11.6 vs. 24.8 for the unexposed; difference in means -13.2 [95% confidence interval (CI) -18.7 to -7.7, P < 0.0001]. Mean surface area involvement at the end of treatment was 11% for the NB-UVB cohort vs. 36% for the unexposed cohort; difference in means -25% (95% CI -34% to -16%, P < 0.0001). Subjective and quality-of-life scores showed significant difference between cohorts at the end of treatment (P < 0.05). Objective scores remained significantly lower than in the unexposed cohort 3 and 6 months after treatment. CONCLUSION: NB-UVB is clinically effective and improves quality of life in children with moderate-to-severe eczema. The effect is maintained for 6 months after treatment.

Molecular epidemiology of bat lyssaviruses in Europe.

Bat rabies cases in Europe are principally attributed to two lyssaviruses, namely European bat lyssavirus type 1 (EBLV-1) and European bat lyssavirus type 2 (EBLV-2). Between 1977 and 2011, 961 cases of bat rabies were reported to Rabies Bulletin Europe, with the vast majority (>97%) being attributed to EBLV-1. There have been 25 suspected cases of EBLV-2, of which 22 have been confirmed. In addition, two single isolations of unique lyssaviruses from European insectivorous bats were reported in south-west Russia in 2002 (West Caucasian bat virus) and in Germany in 2010 (Bokeloh bat lyssavirus). In this review, we present phylogenetic analyses of the EBLV-1 and EBLV-2 using partial nucleoprotein (N) gene sequences. In particular, we have analysed all EBLV-2 cases for which viral sequences (N gene, 400 nucleotides) are available (n = 21). Oropharyngeal swabs collected from two healthy Myotis daubentonii during active surveillance programmes in Scotland and Switzerland also yielded viral RNA (EBLV-2). Despite the relatively low number of EBLV-2 cases, a surprisingly large amount of anomalous data has been published in the scientific literature and Genbank, which we have collated and clarified. For both viruses, geographical relationships are clearly defined on the phylogenetic analysis. Whilst there is no clear chronological clustering for either virus, there is some evidence for host specific relationships, particularly for EBLV-1 where more host variation has been observed. Further genomic regions must be studied, in particular for EBLV-1 isolates from Spain and the EBLV-2 isolates to provide support for the existence of sublineages.

Immunotherapy for allergic rhinitis.

Allergic rhinitis (AR) affects more than 20% of the population in the United Kingdom and western Europe and represents a major cause of morbidity that includes interference with usual daily activities and impairment of sleep quality. This guidance prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) is for the management of AR in patients that have failed to achieve adequate relief of symptoms despite treatment with intranasal corticosteroids and/or antihistamines. The guideline is based on evidence and is for use by both adult physicians and paediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are indications and contraindications for immunotherapy, criteria for patient selection, the evidence for short- and long-term efficacy of subcutaneous and sublingual immunotherapy, and discussion on safety and the different modes of immunotherapy including, pre-seasonal and co-seasonal treatments. There are sections on children, allergen standardization, vaccines used in the United Kingdom, oral allergy syndrome, cost effectiveness of immunotherapy and practical considerations of undertaking immunotherapy including recommendations on who should undertake immunotherapy and dosing schedules. Finally, there is discussion on potential biomarkers of response to immunotherapy, the use of component-resolved diagnostics, novel approaches, alternative routes and potential areas for future research.

Diagnosis and management of hymenoptera venom allergy: British Society for Allergy and Clinical Immunology (BSACI) guidelines.

This guidance for the management of patients with hymenoptera venom allergy has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and pediatricians practising allergy. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are epidemiology, risk factors, clinical features, diagnostic tests, natural history of hymenoptera venom allergy and guidance on undertaking venom immunotherapy (VIT). There are also separate sections on children, elevated baseline tryptase and mastocytosis and mechanisms underlying VIT. Finally, we have made recommendations for potential areas of future research.

Characterization of rabies virus from a human case in Nepal.

Rabies is endemic throughout most of Asia, with the majority of human cases transmitted by domestic dogs (Canis familiaris). Here, we report a case of rabies in a 12-year-old girl in the Lalitpur district of Nepal that might have been prevented by better public awareness and timely post-exposure prophylaxis. Molecular characterization of the virus showed 100% identity over a partial nucleoprotein gene sequence to previous isolates from Nepal belonging to the 'arctic-like' lineage of rabies virus. Sequence analysis of both partial nucleoprotein and glycoprotein genes showed differences in consensus sequence after passage in vitro but not after passage in vivo.

Improved safety for molecular diagnosis of classical rabies viruses by use of a TaqMan real-time reverse transcription-PCR "double check" strategy.

To improve the diagnosis of classical rabies virus with molecular methods, a validated, ready-to-use, real-time reverse transcription-PCR (RT-PCR) assay was developed. In a first step, primers and 6-carboxyfluorescien-labeled TaqMan probes specific for rabies virus were selected from the consensus sequence of the nucleoprotein gene of 203 different rabies virus sequences derived from GenBank. The selected primer-probe combination was highly specific and sensitive. During validation using a sample set of rabies virus strains from the virus archives of the Friedrich-Loeffler-Institut (FLI; Germany), the Veterinary Laboratories Agency (VLA; United Kingdom), and the DTU National Veterinary Institute (Lindholm, Denmark), covering the global diversity of rabies virus lineages, it was shown that both the newly developed assay and a previously described one had some detection failures. This was overcome by a combined assay that detected all samples as positive. In addition, the introduction of labeled positive controls (LPC) increased the diagnostic safety of the single as well as the combined assay. Based on the newly developed, alternative assay for the detection of rabies virus and the application of LPCs, an improved diagnostic sensitivity and reliability can be ascertained for postmortem and intra vitam real-time RT-PCR analyses in rabies reference laboratories.

British Society for Allergy and Clinical Immunology guidelines for the management of egg allergy.

This guideline advises on the management of patients with egg allergy. Most commonly, egg allergy presents in infancy, with a prevalence of approximately 2% in children and 0.1% in adults. A clear clinical history and the detection of egg white-specific IgE (by skin prick test or serum assay) will confirm the diagnosis in most cases. Egg avoidance advice is the cornerstone of management. Egg allergy often resolves and re-introduction can be achieved at home if reactions have been mild and there is no asthma. Patients with a history of severe reactions or asthma should have reintroduction guided by a specialist. All children with egg allergy should receive measles, mumps and rubella (MMR) vaccination. Influenza and yellow fever vaccines should only be considered in egg-allergic patients under the guidance of an allergy specialist. This guideline was prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and is intended for allergists and others with a special interest in allergy. The recommendations are evidence-based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, diagnosis, treatment, prognosis and co-morbid associations.

Aquagenic palmar wrinkling as a presenting feature of cystic fibrosis gene dysfunction.

Aquagenic palmar wrinkling (APW) is characterized by the rapid and transient oedematous wrinkling of the palms after brief immersion in water. APW has been associated with cystic fibrosis (CF). Since the discovery of the CF gene, the clinical spectrum of CF has broadened from classic severe CF to include milder 'atypical CF' and 'CF-related disorders'. We report an unusual case in which APW occurred in a patient with no lung disease, and in whom investigations showed evidence of CF gene dysfunction. APW may be a presenting feature of a CF-related disorder and should prompt investigation of CF gene dysfunction.

BSACI guidelines for the management of allergic and non-allergic rhinitis.

This guidance for the management of patients with allergic and non-allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co-morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research.

A current and online genodermatosis database.

Clinical dermatologists have great difficulty keeping abreast of research in genetic skin disease. This is because there is too much information, in too many places, and in an unfamiliar language. In this review we have simplified and tabulated our current knowledge of the genodermatoses. We hope this 'at a glance' online guide will help dermatologists apply research findings to clinical practice and give informed advice to patients.

14th International HLA and Immunogenetics Workshop: report on the Prospective Chronic Rejection Project.

An international collaborative study of 45 transplant centers was undertaken at the 14th International HLA (human leukocyte antigen) and Immunogenetics Workshop to see if HLA antibodies detected posttransplant are predictive of chronic graft failure. With the newly developed assay, MICA (major histocompatibility complex class I-related chain A) antibodies were also measured and their effect analyzed. Total of 5219 sera from patients who were more than 6 months posttransplant with functioning graft were tested for HLA antibodies by enzyme-linked immunosorbent assay, flow cytometry, or Luminex. HLA antibodies were found in 27.2% of kidney patients, 23.6% in the liver, 52.7% in the heart, and 21.7% in the lung. The method of antibody testing did not have a marked influence on the frequency of antibodies detected. MICA antibodies were detected in 15% of kidney patients, 30% of heart patients, and 31% of liver patients. Among 948 kidney patients who had HLA antibodies, 7.3% had rejected their graft within 1 year of testing, compared with 1.7% in 2615 patients without HLA antibodies (P= 0.8 x 10(-17)). Death occurred in 1.4% of total kidney patients and did not correlate to the presence of antibodies. We conclude that patients with posttransplant HLA antibodies indeed have a higher rate of chronic graft failure and that posttransplant antibodies are predictive of chronic rejection.