Netherton Syndrome in Children: Management and Future Perspectives

Barbati, Federica; Giovannini, Mattia; Oranges, Teresa; Lodi, Lorenzo; Barni, Simona; Novembre, Elio; Baldo, Ermanno; Cristofolini, Mario; Stagi, Stefano; Ricci, Silvia; Mori, Francesca; Filippeschi, Cesare; Azzari, Chiara; Indolfi, Giuseppe

doi:10.3389/fped.2021.645259

Cited by 28 publications

(28 citation statements)

References 81 publications

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“…The prognosis of Netherton syndrome may be severe, with significant mortality in early years of life due to potentially fatal complications. Skin and hair defects persist throughout life, but the disorder usually becomes more manageable with age [ 120 ]. The pathogenesis of the disease is complex involving interactions between the host immune system and host microbiome, such as the excess microbial proteolytic activity in the setting of LEKTI-1 [ 121 ]; there are no specific therapies currently available for patients with Netherton syndrome.…”

Section: Resultsmentioning

confidence: 99%

VEBA: a modular end-to-end suite for in silico recovery, clustering, and analysis of prokaryotic, microeukaryotic, and viral genomes from metagenomes

Espinoza

Dupont

2022

BMC Bioinformatics

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Background With the advent of metagenomics, the importance of microorganisms and how their interactions are relevant to ecosystem resilience, sustainability, and human health has become evident. Cataloging and preserving biodiversity is paramount not only for the Earth’s natural systems but also for discovering solutions to challenges that we face as a growing civilization. Metagenomics pertains to the in silico study of all microorganisms within an ecological community in situ, however, many software suites recover only prokaryotes and have limited to no support for viruses and eukaryotes. Results In this study, we introduce the Viral Eukaryotic Bacterial Archaeal (VEBA) open-source software suite developed to recover genomes from all domains. To our knowledge, VEBA is the first end-to-end metagenomics suite that can directly recover, quality assess, and classify prokaryotic, eukaryotic, and viral genomes from metagenomes. VEBA implements a novel iterative binning procedure and hybrid sample-specific/multi-sample framework that yields more genomes than any existing methodology alone. VEBA includes a consensus microeukaryotic database containing proteins from existing databases to optimize microeukaryotic gene modeling and taxonomic classification. VEBA also provides a unique clustering-based dereplication strategy allowing for sample-specific genomes and genes to be directly compared across non-overlapping biological samples. Finally, VEBA is the only pipeline that automates the detection of candidate phyla radiation bacteria and implements the appropriate genome quality assessments. VEBA’s capabilities are demonstrated by reanalyzing 3 existing public datasets which recovered a total of 948 MAGs (458 prokaryotic, 8 eukaryotic, and 482 viral) including several uncharacterized organisms and organisms with no public genome representatives. Conclusions The VEBA software suite allows for the in silico recovery of microorganisms from all domains of life by integrating cutting edge algorithms in novel ways. VEBA fully integrates both end-to-end and task-specific metagenomic analysis in a modular architecture that minimizes dependencies and maximizes productivity. The contributions of VEBA to the metagenomics community includes seamless end-to-end metagenomics analysis but also provides users with the flexibility to perform specific analytical tasks. VEBA allows for the automation of several metagenomics steps and shows that new information can be recovered from existing datasets.

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Section: Resultsmentioning

confidence: 99%

VEBA: a modular end-to-end suite for in silico recovery, clustering, and analysis of prokaryotic, microeukaryotic, and viral genomes from metagenomes

Espinoza

Dupont

2022

BMC Bioinformatics

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“…A recent systematic review summarized the different therapeutic options for children with NS ( 42 ). Here, we further explore treatment regimens for NS, specifically focusing on systemic treatment options in both children and adults.…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review

et al. 2022

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BackgroundComèl-Netherton syndrome (NS) is a rare disease caused by pathogenic variants in the SPINK5 gene, leading to severe skin barrier impairment and proinflammatory upregulation. Given the severity of the disease, treatment of NS is challenging. Current treatment regimens are mainly topical and supportive. Although novel systemic treatment options for NS have been suggested in recent literature, little is known about their outcomes.Objectiveto provide an overview of systemic treatment options and their outcomes in adults and children with NS.MethodsEmbase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar were searched up to July 22, 2021. Empirical studies published in English language mentioning systemic treatment in NS were enrolled. Studies that did not define a treatment period or report at least one outcome were excluded. Methodological quality was evaluated by the Joanna Briggs Institute critical appraisal checklist for case reports or case series. Overall quality of evidence of the primary outcome, skin, was assessed by the GRADE approach.Results36 case series and case reports were included. The effects of 15 systemic therapies were described in 48 patients, of which 27 were children. Therapies included retinoids, prednisolone, cyclosporine, immunoglobulins, and biologicals. In retinoids both worsening (4/15 cases) and improvement (6/15 cases) of the skin was observed. Use of prednisolone and cyclosporine was only reported in one patient. Immunoglobulins (13/15 cases) and biologicals (18/21 cases) showed improvement of the skin. Certainty of evidence was rated as very low.ConclusionNS is a rare disease, which is reflected in the scarce literature on systemic treatment outcomes in children and adults with NS. Studies showed large heterogeneity in outcome measures. Adverse events were scarcely reported. Long-term outcomes were reported in a minority of cases. Nonetheless, a general beneficial effect of systemic treatment was found. Immunoglobulins and biologicals showed the most promising results and should be further explored. Future research should focus on determining a core outcome set and measurement instruments for NS to improve quality of research.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=217933, PROSPERO (ID: 217933).

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“…NS is an autosomal recessive disease characterized by congenital ichthyosiform erythroderma, hair shaft abnormalities and atopic manifestations (1). It causes lifethreatening complications in the neonatal period and in infancy, e.g., due to severe dehydration, systemic infections and failure to thrive.…”

Section: Introductionmentioning

confidence: 99%

Biological treatments for pediatric Netherton syndrome

et al. 2022

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Netherton syndrome (NS) is a rare and potentially life-threatening genetic skin disease responsible for skin inflammation and scaling, hair abnormalities and severe allergic manifestations. NS is caused by loss-of-function variants in Serine Peptidase Inhibitor Kazal-Type 5 (SPINK5), encoding the serine protease inhibitor LEKTI. NS patients have a profound skin barrier defect caused by unopposed kallikrein-related proteases activity (KLKs). They develop severe skin inflammation with eczematous-like lesions and high serum IgE levels. Multiomics studies have revealed that the IL-17/IL-36 pathway is the most predominant upregulated pathway in NS. It is associated with a Th2 signature with complement activation in the ichthyosis linearis circumflexa subtype, and with interferon and Th9 activation in the scaly erythrodermic form. Several case reports proved the efficacy of different biotherapies targeting IL-17A, IL-12/IL-23, IL-4R and IL-13R, TNF-a and IL-1β in pediatric NS patients. Intravenous immunoglobulins (IVIG) have also shown efficacy. These studies showed no severe side effects. At present, IL-17 blockade seems to be the most efficient treatment, but case reports remain limited with small numbers of patients and no placebo-control. Additional pathways must also be explored, and more efficient strategies could be used to block IL-17 and IL-23 pathways. In the future, the combination of specific strategies aiming at repairing the initial skin barrier defect could potentiate the efficacy of biologics. The current reports suggest that biological therapy is safe and often effective at pediatric age. However, controlled clinical trials that include a larger number of patients need to be conducted to reach more reliable conclusions.

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Netherton Syndrome in Children: Management and Future Perspectives

Cited by 28 publications

References 81 publications

VEBA: a modular end-to-end suite for in silico recovery, clustering, and analysis of prokaryotic, microeukaryotic, and viral genomes from metagenomes

VEBA: a modular end-to-end suite for in silico recovery, clustering, and analysis of prokaryotic, microeukaryotic, and viral genomes from metagenomes

Outcomes of Systemic Treatment in Children and Adults With Netherton Syndrome: A Systematic Review

Biological treatments for pediatric Netherton syndrome

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