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Nethertone syndrome

H Wiegmann, F Valentin, T Tarinski, E Liebau, K Loser, H Traupe, V Oji
BACKGROUND: Transglutaminase 1 (TG1) plays a key role in the formation of the cornified envelope and thus in the maintenance of the epidermal barrier. Patients with Netherton syndrome (LEKTI deficiency) have an increased activity of TG1 as well as of serin proteases. OBJECTIVE: We wondered whether there is a functional biochemical link between TG1 and LEKTI and whether LEKTI domains could possibly serve as substrates for TG1. METHODS: We analysed the protein sequence of LEKTI for possible TG1 recognition sites using bioinformatics...
February 22, 2019: British Journal of Dermatology
Gemma V White, Emma V Edgar, Duncan S Holmes, Xiao Qing Lewell, John Liddle, Oxana Polyakova, Kathrine J Smith, James H Thorpe, Ann L Walker, Yichen Wang, Robert J Young, Alain Hovnanian
Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS...
January 22, 2019: Bioorganic & Medicinal Chemistry Letters
Stephanie Tanner, Atharina Julai, David Angelo Gorard
A 21-year-old man with Netherton syndrome underwent investigation of a persistently elevated serum alanine transaminase, detected on routine monitoring. He drank no alcohol, was not diabetic or overweight (body mass index 23 kg/m2 ) and had no clinical features of liver dysfunction. A FibroScan yielded an elevated result of 9.3 kPa. An ultrasound guided liver biopsy showed histological features consistent with non-alcoholic steatohepatitis, with activity score of 4 and fibrosis stage of 3. The patient was started on vitamin E supplementation and remains under surveillance...
November 28, 2018: BMJ Case Reports
Elina Eränkö, Mette Ilander, Mirja Tuomiranta, Antti Mäkitie, Tea Lassila, Anna Kreutzman, Paula Klemetti, Satu Mustjoki, Katariina Hannula-Jouppi, Annamari Ranki
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...
November 26, 2018: Orphanet Journal of Rare Diseases
Debra Crumrine, Denis Khnykin, Peter Krieg, Mao-Qiang Man, Anna Celli, Theodora M Mauro, Joan S Wakefield, Gopinathan Menon, Elizabeth Mauldin, Jeffrey H Miner, Meei-Hua Lin, Alan R Brash, Eli Sprecher, Franz P W Radner, Keith Choate, Dennis Roop, Yoshikazu Uchida, Robert Gruber, Matthias Schmuth, Peter M Elias
The corneocyte lipid envelope (CLE), a monolayer of ϖ-hydroxyceramides, whose function(s) remain(s) uncertain, is absent in autosomal recessive congenital ichthyoses (ARCI) with mutations in enzymes that regulate epidermal lipid synthesis. Secreted lipids fail to transform into lamellar membranes in certain ARCI epidermis, suggesting the CLE provides a scaffold for the extracellular lamellae. But since cornified envelopes (CEs) are attenuated in these ARCI, the CLE may also provide a scaffold for subjacent CE formation, evidenced by restoration of CEs after CLE 'rescue...
November 21, 2018: Journal of Investigative Dermatology
Eleni Zingkou, Georgios Pampalakis, Dimitra Kiritsi, Manthoula Valari, Nathalie Jonca, Georgia Sotiropoulou
The role of epidermal proteolysis in overdesquamation was revealed in Netherton syndrome, a rare ichthyosis due to genetic deficiency of the LEKTI inhibitor of serine proteases. Recently, we developed activography, a new histochemical method, to spatially localize and semi-quantitatively assess proteolytic activities using activity-based probes. Activography provides specificity and versatility compared to in situ zymography, the only available method to determine enzymatic activities in tissue biopsies. Here, activography was validated in skin biopsies obtained from an array of distinct disorders and compared with in situ zymography...
November 3, 2018: Experimental Dermatology
Hafiz M Kashif Saleem, Muhammad Faizan Shahid, Amir Shahbaz, Atif Sohail, Muhammad Arslan Shahid, Issac Sachmechi
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...
July 30, 2018: Curēus
Saeko Sugimoto, Shin Morizane, Hayato Nomura, Mina Kobashi, Satoru Sugihara, Keiji Iwatsuki
BACKGROUND: Lympho-epithelial Kazal-type inhibitor (LEKTI) tightly controls the activities of serine proteases such as kallikrein-related peptidase (KLK) 5 and KLK7 in the epidermis. LEKTI is known to be an essential molecule for the epidermal skin barrier, as demonstrated by SPINK5 nonsense mutation, which results in Netherton syndrome. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns or damage-associated molecular patterns and produce inflammatory cytokines, chemokines, and antimicrobial peptides...
September 15, 2018: Journal of Dermatological Science
Chiaki Murase, Takuya Takeichi, Akitaka Shibata, Masahiro Nakatochi, Fumie Kinoshita, Akiharu Kubo, Kimiko Nakajima, Norito Ishii, Hiroo Amano, Koji Masuda, Hiroshi Kawakami, Takuro Kanekura, Ken Washio, Masayuki Asano, Kazuya Teramura, Eijiro Akasaka, Mikiko Tohyama, Yutaka Hatano, Toyoko Ochiai, Shinichi Moriwaki, Tomotaka Sato, Akemi Ishida-Yamamoto, Mariko Seishima, Michiko Kurosawa, Shigaku Ikeda, Masashi Akiyama
BACKGROUND: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. OBJECTIVE: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan...
September 11, 2018: Journal of Dermatological Science
Josette Jwm Versteegh, Karolijn Dulfer, Kira Stuvel, Suzanne Gma Pasmans, Elisabeth Mwj Utens
BACKGROUND: Netherton syndrome is a rare severe skin disease. Clinical experience showed considerable psychosocial burdens among Netherton syndrome patients/families. Their (neuro)psychological functioning has never been investigated. OBJECTIVE: To investigate neuropsychological/psychosocial functioning of Netherton syndrome patients and parents. METHODS: A total of 12 Netherton syndrome patients and/or parents completed neuropsychological tests, semi-structured-interviews, and psychological-questionnaires...
August 21, 2018: Journal of Health Psychology
Jing Wu, Li Hong, Tong-Xin Chen
PURPOSE OF REVIEW: The hyper IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders (PIDDs), which are characterized by extremely high serum IgE levels, eczema, recurrent skin and pulmonary infections. Both autosomal dominant (AD) HIES due to STAT3 mutations and autosomal recessive (AR) HIES due to PGM3, SPINK5, DOCK8 and TKY2 mutations have been reported. Here, we aim to summarize and compare the major clinical manifestations of different subtypes of HIES. We will also discuss otitis media, which usually do not get enough attention in HIES...
August 15, 2018: Current Allergy and Asthma Reports
Emel Okulu, Gaffari Tunc, Omer Erdeve, Yelda Mumcu, Begum Atasay, Erdal Ince, Saadet Arsan
Netherton syndrome (NS) is a rare, autosomal recessive disease characterized with congenital ichthyosiform erythroderma, hair abnormality and atopic manifestations. This syndrome is caused by recessive mutation in the SPINK5 gene. Disease manifestations vary considerably among NS individuals. We report a newborn presented with severe respiratory insufficiency, hypothermia and erythroderma, was diagnosed as having NS and confirmed with molecular genetic testing.
August 1, 2018: Archivos Argentinos de Pediatría
Shin Morizane, Mamoru Ouchida, Ko Sunagawa, Saeko Sugimoto, Mina Kobashi, Satoru Sugihara, Hayato Nomura, Kazuhide Tsuji, Atsushi Sato, Yoshihiro Miura, Hiroaki Hattori, Kotaro Tada, Wook-Kang Huh, Akemi Seno, Keiji Iwatsuki
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a large multidomain serine protease inhibitor that is expressed in epidermal keratinocytes. Nonsense mutations of the SPINK5 gene, which codes for LEKTI, cause Netherton syndrome, which is characterized by hair abnormality, ichthyosis, and atopy. A single nucleotide polymorphism (SNP) of SPINK5, p.K420E, is reported to be associated with the pathogenesis of atopic dermatitis (AD). We studied all 34 exons of the SPINK5 gene in Japanese 57 AD patients and 50 normal healthy controls...
June 2018: Acta Medica Okayama
Kunal Malik, Helen He, Thy Nhat Huynh, Gary Tran, Kelly Mueller, Kristina Doytcheva, Yael Renert-Yuval, Tali Czarnowicki, Shai Magidi, Margaret Chu, Yeriel D Estrada, Huei-Chi Wen, Xiangyu Peng, Hui Xu, Xiuzhong Zheng, James G Krueger, Amy S Paller, Emma Guttman-Yassky
BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: To profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma/CIE, n=9; lamellar ichthyosis/LI, n=8; epidermolytic ichthyosis/EI, n=8; and Netherton syndrome/NS, n=4), as well as age-matched healthy controls (n=14), psoriasis (n=30), and atopic dermatitis/AD (n=16) patients...
May 24, 2018: Journal of Allergy and Clinical Immunology
Carmelo Schepis, Pinella Failla, Maddalena Siragusa, Mirella Vinci, Francesco Calì
No abstract text is available yet for this article.
May 16, 2018: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
Tali Czarnowicki, Helen He, Alexandra Leonard, Kunal Malik, Shai Magidi, Stephanie Rangel, Krishna Patel, Kara Ramsey, Morgan Murphrey, Teresa Song, Yeriel Estrada, Hue-Chi Wen, James G Krueger, Emma Guttman-Yassky, Amy S Paller
The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4+ /CD8+ and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+ /CD8+ T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively...
April 14, 2018: Journal of Investigative Dermatology
Alexander K C Leung, Benjamin Barankin, Kin Fon Leong
We report an 8-year-old boy with Netherton syndrome who was misdiagnosed and treated as severe atopic dermatitis. The diagnosis of Netherton syndrome was not made until the child was 8 years of age. We discuss the pitfalls in the diagnosis and alert physicians to the proper and early diagnosis of this syndrome. The child was treated with a low dose (0.25 mg/kg) of oral acitretin and a topical moisturizer with marked improvement of his skin and pruritus in 2 months. At 6-month follow-up, the skin was almost clear of erythema and scaling, and the hair was longer and stronger...
2018: Case Reports in Pediatrics
David Ulbricht, Catherine A Tindall, Kathrin Oertwig, Stefanie Hanke, Norbert Sträter, John T Heiker
Kallikrein-related peptidases KLK5, KLK7 and KLK14 are important proteases in skin desquamation and aberrant KLK activity is associated with inflammatory skin diseases such as Netherton syndrome but also with various serious forms of cancer. Previously, we have identified KLK7 as the first protease target of vaspin (Serpin A12). Here, we report KLK14 as a second KLK protease to be inhibited by vaspin. In conclusion, vaspin represents a multi-specific serpin targeting the kallikrein proteases KLK7 and KLK14, with distinct exosites regulating recognition of these target proteases and opposing effects of heparin binding on the inhibition reaction...
September 25, 2018: Biological Chemistry
Olivier Gouin, Killian L'Herondelle, Paul Buscaglia, Christelle Le Gall-Ianotto, Réginald Philippe, Nelig Legoux, Olivier Mignen, Virginie Buhé, Raphael Leschiera, Mehdi Sakka, Nathalie Kerfant, Jean-Luc Carré, Raphaele Le Garrec, Luc Lefeuvre, Nicolas Lebonvallet, Laurent Misery
PAR2 activation in basal keratinocytes stimulates inflammation via the Ca2+ -dependent production of mediators such as IL-1β, TNF-α, and TSLP. In this study, we investigated PAR2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR2-activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes and DhPKs. SLIGKV-evoked Ca2+ store depletion did not trigger the store-operated Ca2+ entry (i...
July 2018: Journal of Investigative Dermatology
Akemi Ishida-Yamamoto, Satomi Igawa, Mari Kishibe, Masaru Honma
Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors...
April 2018: Journal of Dermatology
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