A novel <i>SPINK5</i> mutation and successful subcutaneous immunoglobulin replacement therapy in a child with Netherton syndrome

Zelieskova, Maria; Bánovčin, Peter; Kozar, Marek; Kozárová, Andrea; Nudzajova, Zuzana; Jeseňák, Miloš

doi:10.1111/pde.14318

Cited by 11 publications

(9 citation statements)

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“…Several case studies report immunoglobulin replacement therapy of NS patients (mainly newborns and children), the majority of them describing a remarkable clinical response with no major adverse effects [16,19,283,284].…”

Section: Immunoglobulin Replacement Therapymentioning

confidence: 99%

Advances in understanding of Netherton syndrome and therapeutic implications

Petrova

Hovnanian

2020

Expert Opinion on Orphan Drugs

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Introduction: Netherton syndrome (NS) is a rare and severe ichthyosis characterized by superficial scaling, skin inflammation, a specific hair shaft defect, severe atopic manifestations and multisystemic complications. It is an orphan disease with currently no satisfactory treatment. NS is caused by loss-offunction mutations in SPINK5 encoding the serine protease inhibitor LEKTI. NS patients present with ichthyosiform erythroderma or ichthyosis linearis circumflexa and show considerable clinical variability. Areas covered: Uncontrolled serine protease activity leads to a profound skin barrier defect and the release of pro-inflammatory and pro-allergic mediators by keratinocytes and immune cells. Improved understanding of NS pathogenesis has led to the successful use of repurposed biologics such as intravenous immunoglobulins and anti-IL-17A blockers. Between April 1, 2020 and November 18, 2020, authors searched for NS-relevant information in the following databases: MEDLINE, DrugBank, ClinicalTrials.gov, and patent datasets accessed through lens.org. Expert opinion: Specific KLK5 and/or KLK7 inhibitors represent the most promising disease-modifying treatments. They are currently being developed by several companies. Comprehension of the determinants of NS variability, flares and modification over time will be the foundation for precision medicine. While improved knowledge of the inflammatory and allergic pathways involved is still needed, clinical trials using repurposed biologics have already begun.

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Section: Immunoglobulin Replacement Therapymentioning

confidence: 99%

Advances in understanding of Netherton syndrome and therapeutic implications

Petrova

Hovnanian

2020

Expert Opinion on Orphan Drugs

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“…Furthermore, a decrease in itch and infections, decrease in use of topical steroids, improvement of the quality of hair, and improvement in overall quality of life and functioning was reported (see Tables 1 , S2 ). Remarkably, in 5 children, aged between 4 months and 2 years, a significant increase in weight and height was noted ( 29 , 54 , 72 ). This effect might be attributed to a general improvement in NS symptoms, thereby enabling growth.…”

Section: Discussionmentioning

confidence: 96%

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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“…A previous review revealed improvements in 61% of AD patients treated with IVIG (Jolles, 2002). Previous studies have also reported subcutaneous immunoglobulin substitution (SCIg) was effective in some patients with NS and revealed that SCIg appeared to be a suitable and safe alternative in patients with generalized skin diseases associated with primary immunodeficiencies and difficult intravenous access (Zelieskova et al, 2020). Further understanding of the underlying pathophysiology of integumentary changes will lead to more effective treatment in NS.…”

Section: Discussionmentioning

confidence: 99%

Netherton syndrome caused by compound heterozygous mutation, c.80A>G mutation in SPINK5 and large‐sized genomic deletion mutation, and successful treatment of intravenous immunoglobulin

Zhang

Pan

Wei

et al. 2021

Molec Gen & Gen Med

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Background Netherton syndrome (NS) is an autosomal recessive disorder due to mutations in the SPINK5 gene. Here, we report the first case of NS caused by a large genomic deletion. Methods We present the clinical data of a 3‐year‐old Chinese boy who was initially misdiagnosed with severe atopic dermatitis. Subsequently, the patient presented with typical ichthyosis linearis circumflexa and had representative hair shaft of trichorrhexis invaginate, which alerted the physician of the high possibility of NS. A genomic DNA sample was extracted from peripheral blood and whole‐exome sequencing (WES) was performed. Sanger sequencing and quantitative real‐time polymerase chain reaction (qRT‐PCR) were performed to verify the mutation and genomic deletion, respectively, in the pedigree. Results WES revealed compound heterozygous mutations in SPINK5, including a c.80A>G mutation and a ~275 Kb‐sized genomic deletion (chr5:147443576‐147719312). The c.80A>G mutation was verified by Sanger sequencing in the pedigree. The father had the same heterozygous mutation; however, the mutation was absent in the proband's mother. The qRT‐PCR results identified a large deletion (chr5:147444834‐147445034) in SPINK5 in the proband and his mother. The eruptions improved remarkably after intravenous immunoglobulin (IVIG) therapy. Conclusions This is the first observation of NS caused by a large deletion. Our findings have important implications for mutation screening and genetic counseling in NS. Our report also verifies and supports the safety and efficacy of IVIG therapy in patients with NS.

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A novel SPINK5 mutation and successful subcutaneous immunoglobulin replacement therapy in a child with Netherton syndrome

Cited by 11 publications

References 5 publications

Advances in understanding of Netherton syndrome and therapeutic implications

Advances in understanding of Netherton syndrome and therapeutic implications

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

Netherton syndrome caused by compound heterozygous mutation, c.80A>G mutation in SPINK5 and large‐sized genomic deletion mutation, and successful treatment of intravenous immunoglobulin

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