Explore the vast range of titles available.

Abstract Introduction: Netherton syndrome (NS) is a rare autosomal recessive genodermatosis in the group of congenital ichthyosis. The clinical manifestations of the syndrome vary from a very mild clinical manifestation occurring with the picture of ichthyosis linearis circumflexa to exfoliative erythroderma. It can be fatal in the first days of a newborn’s life due to dehydration, hypothermia, weight loss, respiratory infections, and sepsis. A specific anomaly of the hair trichorrexis invaginata is considered pathognomonic for the syndrome. Genetic testing of SPINK5 gene is key to confirming the diagnosis and starting early treatment. Case Presentation: We present a case report of NS in a 6-year-old boy who suffered from generalized erythroderma and desquamation of the skin from birth. The patient has atopic diathesis, recurrent skin infections, increased levels of IgE, and delayed physical development. Two genetic variants in SPINK5 gene with clinical significance were identified. The first detected variant is a nonsense mutation, predicted to cause loss of normal protein function either by protein truncation or by nonsense-mediated mRNA decay. The second variant is a likely pathogenic frameshift mutation that truncates the protein in 5 amino acids. The child was treated with acitretin, without satisfactory effect. Conclusion: The genetic variant we have described correlates with a severe clinical phenotype of NS. The second genetic variant of the SPINK5 gene, inherited from the father in our case, is novel and has never been published in the literature.

Netherton syndrome (NS) is a rare genodermatosis characterized by the triad of ichthyosiform erythroderma, hair shaft abnormality and an atopic diathesis. We report a case of a 20-year-old male patient presented with pruritus, decreased sweat secretion and generalized erythema on his body. Netherton syndrome is caused by mutations in the gene that is a crucial role for epidermal barrier function in the skin. Different clinical and phenotypical features can occur based on various LEKTI-domains mutations. Diagnosis is made by the atopic story, hair shaft abnormality, cutaneous lesions and identification of the gene mutation. In our patient, we detected a new splice site mutation in the gene and pili annulati as hair abnormality. Affected patients are usually misdiagnosed because of cutaneous lesions such as atopic dermatitis. Therefore, each clinical finding should be evaluated together. We aimed to present a case with a new gene mutation and different clinical features in NS.

Netherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets. To evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment. Four children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis. All four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0-83.9%) and NRS (by 87.5-90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6-86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment ( = 0.029). The baseline percentage of Th2 cells (among total CD3 CD4 T cells) was significantly higher in patients than that in healthy controls (HC) ( < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events. Dupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.

Netherton syndrome (NS) is a rare autosomal recessive disorder caused by mutations in the gene, which encodes the serine protease inhibitor LEKTI. It is characterized by congenital ichthyosis, hair shaft abnormalities, and atopic manifestations. Previous reports suggest that intravenous immunoglobulin (IVIG) may provide partial clinical benefit in NS. Here, we report the clinical and immunological characterization of an infant with NS effectively treated with IVIG therapy. Clinical information was collected and reviewed from a 1-year-6-month-old boy presenting with NS. Hair shaft abnormalities were examined by scanning electron microscopy. Pathogenic variants in were identified using whole-exome and Sanger sequencing. Protein expression was assessed by Western blotting and ELISA. Peripheral lymphocyte subsets were analyzed by flow cytometry, and cytokine levels were evaluated with the Olink® Target 48 Cytokine panel. The patient presented with typical clinical manifestations of NS. Genetic analysis identified a novel heterozygous deletion spanning the gene (chr5:147,443,561-147,719,327), together with the c.1258A>G (p.K420E) polymorphism. LEKTI expression was markedly decreased, consistent with the genetic findings. Immune profiling revealed markedly reduced unswitched memory and marginal zone-like B cells, increased naïve B cells, and elevated γδ T cells compared with healthy controls. Cytokine analysis showed significantly increased levels of multiple pro-inflammatory cytokines, including TGFA, IL17 family members, CXCL8, CCL2, TNF, CCL19, and IL18. Following IVIG therapy, the patient demonstrated significant clinical improvement, with recovery of skin manifestations, and partial normalization of lymphocyte subsets and cytokine levels, indicating restoration of immune regulation. This study reports a novel compound heterozygous mutation in an infant with NS, comprising a large deletion and c.1258A>G polymorphism, resulting in LEKTI deficiency and immune dysregulation. IVIG therapy effectively alleviated clinical symptoms and restored immune balance, highlighting its potential as a therapeutic option for NS and related immunodeficiency disorders.

We describe here eleven different mutations in SPINK5 , encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.

Netherton syndrome (NS) is a rare, autosomal recessive genodermatosis resulting from mutations in the SPINK5 gene, which encodes the LEKTI (Lympho-Epithelial Kazal-type-related inhibitor) protein. This deficiency leads to dysregulated epidermal protease activity, primarily of kallikrein-related peptidases (KLKs), causing severe skin barrier defects, abnormal desquamation, and a complex immune dysregulation involving the T 2 and T 17 pathways. Clinically, NS is characterised by a triad of ichthyosiform erythroderma (often evolving from congenital ichthyosiform erythroderma to ichthyosis linearis circumflexa); pathognomonic hair shaft abnormalities, such as trichorrhexis invaginata (“bamboo hair”); and atopic manifestations with elevated serum IgE. Diagnosis can be challenging due to symptomatic overlap with other inflammatory dermatoses, congenital ichthyosis, and primary immunodeficiencies. Confirmation relies on clinical findings, trichoscopic hair examination, and SPINK5 genetic testing. Management is currently largely supportive, focusing on emollients, antiseptics, and cautious use of topical anti-inflammatory agents. While traditional systemic treatments have limitations, emerging targeted therapies, including biologics and gene therapy, show promise, but require further investigation through robust clinical trials to establish their efficacy and safety. This review highlights the diagnostic intricacies and evolving therapeutic landscape of this complex disorder.

Netherton Syndrome (NS) is a very rare genetic skin disease resulting from defects in the gene (encoding the protease inhibitor lympho-epithelial Kazal type inhibitor 1, LEKTI1). In this report, we provide a detailed clinical description of a Polish patient with two mutations, the novel c.1816_1820+21delinsCT and possibly recurrent c.1431-12G>A. A detailed pathogenesis of Netherton Syndrome, on the basis of literature review, is discussed in the view of current knowledge about the LEKT1 molecular processing and activity.

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. We report the detection of compound heterozygous mutations, c.80A>G mutation in SPINK5 gene in one allele and the ~275 Kb large‐sized deletion mutation in another allele in a 3‐year‐old boy with Netherton syndrome. After the intravenous immunoglobulin therapy, eruptions were improved remarkably in this patient with Netherton syndrome.

Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma and atopic dermatitis (AD). Mutations in the gene encoding serine protease inhibitor Kazal-type 5 (SPINK5) are responsible for Netherton syndrome, a rare skin disorder characterized by greatly elevated IgE levels with atopic manifestations. A recent study of Caucasian AD families showed that maternally derived alleles of the SPINK5 gene are associated with development of AD and asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPINK5 gene. We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population. Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma. Our data indicate that the SPINK5 gene is associated with AD across ethnicities.

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis, and frequent bacterial infections. The disease is caused by mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene, a new type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. We report one Chinese adult with NS. The patient had typical manifestation of NS except for trichorrhexis invaginata with an atopic diathesis and recurrent staphylococcal infections since birth. To evaluate the gene mutation and of its product activity of SPINK5 gene in confirmation of the diagnosis of one Chinese adult with NS. To screen mutations in the SPINK5 gene, 33 exons and flanking intron boundaries of SPINK5 were amplified with polymerase chain reaction (PCR) and used for direct sequencing. In addition, immunohistochemical staining of LEKTI (lymphoepithelial Kazal-type-related inhibitor) with specific antibody was used to confirm the diagnosis of NS. The results were compared with that of healthy individuals (twenty-five blood samples). A G318A mutation was found at exon 5 of patient's SPINK5 gene which is a novel missense mutation. The PCR amplification products with mutation-specific primer were obtained only from the DNA of the patients and their mother, but not from their father and 25 healthy individuals. Immunohistochemical studies indicated there was no LEKTI expression in NS patient's skin and there was a strong LEKTI expression in the normal human skin. In this report, we describe heterozygous mutation in the SPINK5 gene and expression of LEKTI in one Chinese with NS. The results indicate that defective expression of LEKTI in the epidermis and mutations of SPINK5 gene are reliable for diagnostic feature of NS with atypical clinical symptoms.