Scalp roof tiles.: A new diagnostic sign in neonates with Netherton Syndrome.
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ABSTRACT: Clinical presentation
A 2-month-old baby boy, of full-term spontaneous vaginal delivery, presented to the dermatology outpatient clinic with generalized erythroderma, which had been noted since birth. Family history was positive for similar disease in his eldest sister, who died at 6 months of age without a diagnosis. On examination, the patient looked ill with generalized erythroderma, yet there were no signs of ectropion, eclabium, or deformed ears. Diffuse scalp scaling was observed with interlocking tessellation scales over the scalp (Figure 1). Hair microscopy showed in Figure 2. All laboratory results were normal.
SUBMITTER: Al-Khenaizan S
PROVIDER: S-EPMC8128646 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceNetherton syndrome (NS) is a rare, severe genetic disorder of cornification with high morbidity. Treatment for NS has been notoriously difficult. Recent studies showed an upregulated helper T cell (TH) 17/interleukin 23 (IL-23) pathway in NS, suggesting the possibility of treatment strategies that target IL-17.ObjectiveTo evaluate the clinical response of NS to treatment with the IL-17 antagonist secukinumab.Design, setting, and participantsThis case series study reports the experience of compassionate use therapy with secukinumab in 4 patients with severe NS, including 2 children, from December 1, 2018, to December 1, 2019, with 3 patients still undergoing treatment at the time of final analysis. Data were analyzed from December 1, 2018, to December 1, 2019.Main outcomes and measuresExpression of IL-17 in the skin was evaluated by immunohistochemical analysis, and serum cytokine concentrations were measured using a commercially available assay. Treatment response was assessed using the Ichthyosis Area and Severity Index (IASI) total score, including measures of erythema and scaling, the Dermatology Life Quality Index (DLQI), and the 5-D itch scale.ResultsIn all 4 patients (age range, 9-27 years; 3 male and 1 female), immunostaining with an IL-17A antibody showed an increased number of positive cells in lesional skin. Cytokine assessment in serum samples revealed increased levels of CCL20. Treatment duration with secukinumab was 3 to 12 months at the time of this report. After 3 months of therapy, IASI scores were reduced by 44% to 88%, DLQI scores were reduced by 40% to 76%, and 5-D itch scale scores were reduced by 27% to 62%. This outcome was sustained at the 6-month follow-up. Two patients with an erythrodermic phenotype showed marked improvement of all parameters. A refractory palmoplantar eczematous eruption occurred in 2 patients, and a candidal nail infection developed in 2 patients. No severe adverse events were reported.Conclusions and relevanceThis initial case series reporting the use of anti-IL-17 therapy in NS demonstrated marked cutaneous improvement, particularly in 2 pediatric patients with erythrodermic phenotypes. Further studies are needed to evaluate the long-term benefit of this potential treatment modality.
| S-EPMC7254452 | biostudies-literature
Project description:To investigate the effect in the patients with Netherton syndrome, four different patients was evaluated at two time points using single-cell RNA sequencing.
2022-12-28 | GSE214985 | GEO
Project description:Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin desquamation, inflammation, allergic manifestations and hair shaft defects. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. LEKTI deficiency results in unopposed activities of kallikrein-related peptidases (KLKs) and aberrantly increased proteolysis in the epidermis. Spink5?/? mice recapitulate the NS phenotype, display enhanced epidermal Klk5 and Klk7 protease activities and die within a few hours after birth because of a severe skin barrier defect. However the contribution of these various proteases in the physiopathology remains to be determined. In this study, we developed a new murine model in which Klk5 and Spink5 were both knocked out to assess whether Klk5 deletion is sufficient to reverse the NS phenotype in Spink5?/? mice. By repeated intercrossing between Klk5?/? mice with Spink5?/? mice, we generated Spink5?/?Klk5?/? animals. We showed that Klk5 knock-out in Lekti-deficient newborn mice rescues neonatal lethality, reverses the severe skin barrier defect, restores epidermal structure and prevents skin inflammation. Specifically, using in situ zymography and specific protease substrates, we showed that Klk5 knockout reduced epidermal proteolytic activity, particularly its downstream targets proteases KLK7, KLK14 and ELA2. By immunostaining, western blot, histology and electron microscopy analyses, we provide evidence that desmosomes and corneodesmosomes remain intact and that epidermal differentiation is restored in Spink5?/?Klk5?/?. Quantitative RT-PCR analyses and immunostainings revealed absence of inflammation and allergy in Spink5?/?Klk5?/? skin. Notably, Il-1?, Il17A and Tslp levels were normalized. Our results provide in vivo evidence that KLK5 knockout is sufficient to reverse NS-like symptoms manifested in Spink5?/? skin. These findings illustrate the crucial role of protease regulation in skin homeostasis and inflammation, and establish KLK5 inhibition as a major therapeutic target for NS.
| S-EPMC4577096 | biostudies-literature
Project description:Netherton syndrome (NS) is a rare, life-threatening syndrome caused by serine protease inhibitor Kazal-type 5 gene (SPINK 5) mutations, resulting in skin barrier defect, bacterial skin infections, and allergic sensitization in early childhood. Recent data on adult patients with NS suggest that the presence of Staphylococcus aureus further promotes barrier disruption and skin inflammation. We analyzed the skin microbiota by shotgun sequencing in 12 patients with NS from eight Finnish families with healthy family controls as the reference and correlated the findings with allergen-specific IgE prevalence, immune cell phenotype, and infection history of the patients. Compared with healthy family controls, skin microbiome diversity and normal skin site variability were measurably decreased in patients with NS. No correlation was found between allergic sensitization and skin microbiota as such, but low circulating CD57+ and/or CD8+ T cells significantly correlated with lower microbial diversity and less abundance of S. aureus (P < 0.05). S. aureus was the most prevalent species in patients with NS but also Streptococcus agalactiae was abundant in four patients. The genomic DNA relative abundance of S. aureus secreted virulence peptides and proteases PSMα, staphopain A, and staphopain B were increased in most of the samples of patients with NS, and their abundance was significantly (P < 0.05) associated with recurrent childhood skin infections, confirming the clinical relevance of S. aureus dominance in the NS skin microbiome.
| S-EPMC8659401 | biostudies-literature
Project description:Netherton syndrome (NS) is a rare, life-threatening syndrome caused by serine protease inhibitor Kazal-type 5 gene (SPINK 5) mutations, resulting in skin barrier defect, bacterial skin infections, and allergic sensitization in early childhood. Recent data on adult patients with NS suggest that the presence of Staphylococcus aureus further promotes barrier disruption and skin inflammation. We analyzed the skin microbiota by shotgun sequencing in 12 patients with NS from eight Finnish families with healthy family controls as the reference and correlated the findings with allergen-specific IgE prevalence, immune cell phenotype, and infection history of the patients. Compared with healthy family controls, skin microbiome diversity and normal skin site variability were measurably decreased in patients with NS. No correlation was found between allergic sensitization and skin microbiota as such, but low circulating CD57+ and/or CD8+ T cells significantly correlated with lower microbial diversity and less abundance of S. aureus (P < 0.05). S. aureus was the most prevalent species in patients with NS but also Streptococcus agalactiae was abundant in four patients. The genomic DNA relative abundance of S. aureus secreted virulence peptides and proteases PSMα, staphopain A, and staphopain B were increased in most of the samples of patients with NS, and their abundance was significantly (P < 0.05) associated with recurrent childhood skin infections, confirming the clinical relevance of S. aureus dominance in the NS skin microbiome.
| S-EPMC8659401 | biostudies-literature
Project description:Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by a triad of congenital ichthyosiform erythroderma (CIE) or ichthyosis linearis circumflexa (ILC), hair shaft abnormalities, and atopic diathesis (elevated serum IgE ). We report a case of a two-year-old boy presented with intractable pruritus, scaling, dry skin and generalized eczematous lesions resistant to atopic dermatitis therapy. Netherton syndrome misdiagnosed as atopic dermatitis due to the presence of eczematous skin lesions and allergic problems. The family counseled about the diagnosis and need of genetic testing for confirmation, but they refused for genetic testing. The patient got treatment with topical corticosteroids and skin moisturizers. There is no cure or satisfactory treatment currently available for NS. Further understanding of the underlying pathophysiology of integumentary changes will lead to more effective treatment. Netherton syndrome should be in the differential diagnosis when characteristic skin manifestation of CIE or ILC, and elevated serum IgE present.
| S-EPMC6166913 | biostudies-literature
Project description:BACKGROUND:Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete. RESULTS:We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17?years, and healthy age-matched controls. The proportion of B cells (CD19+) and naïve B cells (CD27-, IgD+) were high while memory B cells (CD27+) and switched memory B cells (CD27+IgM-IgD-), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21low, CD38low) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4+ T cells was reduced significantly and the proportion of CD8+ T central memory significantly elevated. An increased proportion of CD57+ CD8+ T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16+ and CD27- NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L+ T cells, naïve CD4+ and CD27+ CD8+ T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8+ cells and decreased the proportion of activated B cells and plasmablasts in three patients studied. CONCLUSIONS:This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.
| S-EPMC6258305 | biostudies-literature
Project description:SKIN MICROBIOTA AND CLINICAL ASSOCIATIONS IN NETHERTON SYNDROME
| PRJEB39614 | ENA
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Project description:Ceramic roof tiles are widespread marketed building materials, rapidly colonized by microorganisms that form multispecies biofilms on their surface and play crucial roles in biodeterioration processes. Coating tiles with water repellents is a pervasive industrial strategy employed to prevent liquid water penetration and slow biodeterioration. Very few studies have examined the links between the characteristics of water-repellent coatings and biofilm colonization patterns. Our work aims to compare the effects of coating tiles with two common water repellents (siliconate and siloxane) on the growth of colonizing microbes. We combined in situ exposure of tiles for over six years and macroscopic and microscopic observations with in vitro biotests, relying on the use of algal and fungal models. Our data showed that (1) tiles coated with water repellents were macroscopically less colonized by lichens (2) a significant fungal biofilm development at the microscopic scale (3) water repellents had very contrasting effects on our model strains. These data reinforce the great interest for industry to conduct more studies linking the nature of the water repellents with the composition of colonizing multispecies biofilms. The long-term objective is to improve the available water repellents and better adapt their selection to the nature of microbial colonization.
| S-EPMC7918968 | biostudies-literature