Peeling Skin Syndrome Type Research Articles

A case of peeling skin syndrome type 1 with novel CDSN gene variation successfully treated with upadacitinib.

Peeling skin syndrome type 1 (PSS1) is an autosomal recessive genodermatosis caused by the CDSN gene loss-of-function mutation and characterized by widespread superficial skin peeling and erythroderma with unbearable pruritus. Because of its ultra-rarity and unclear mechanism, this rare disease has no established treatment regimen. Herein, we reported a Chinese woman who presented with congenital generalized pruritic erythroderma and exfoliation, notable for significantly elevated IgE levels. The whole exome sequencing identified an unpublished homozygous variant (c.295C>T, p.Gln99*) in the CDSN gene, confirming the diagnosis of PSS1. Immunohistochemistry analysis of the affected skin confirmed the lack of corneodesmosin expression, revealed the overexpression of T helper 2 (Th2)-related cytokines harboring interleukin (IL) 4 and IL-13. After Janus kinase 1 (JAK1) inhibitor upadacitinib administration, both the patient's skin rashes and itching symptoms were significantly alleviated. Our work expanded the PSS1-related CDSN gene mutation spectrums, substantiated the hypothesis regarding the overexpression of Th2-related cytokines, and uncovered the important role of JAK1 underlying PSS1. JAK1 signaling may dominate the pathogenesis in PSS1 and represent a potential therapeutic target.

Development of a protein replacement therapy for peeling skin syndrome

British Journal of DermatologyVolume 184, Issue 6 p. e197-e197 Plain Language SummaryFree Access Development of a protein replacement therapy for peeling skin syndrome First published: 06 June 2021 https://doi.org/10.1111/bjd.20101AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract Linked article: Valentin et al. Br J Dermatol 2021; 184:1123–1131. Peeling skin syndrome type 1 is a severe form of congenital ichthyosis. Patients have severe itch and generalized peeling of the skin. Current therapeutic approaches are very unsatisfactory. The disease is the result of mutations (mistakes) in the CDSN gene, which cause a lack of the protein corneodesmosin (CDSN) in the skin. We wanted to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. The aim is to improve the cell–cell connection in two layers of the epidermis (the granular and corneal layers). Human CDSN was produced in bacterial cells. A liposomal carrier system was developed to transport the CDSN to the outer membrane of the epidermal cells. The liposomal carrier system was checked for stability and toxicity. Also, the effect on epidermal cells and artificial skin models was investigated. The liposomes were found to be successfully present at the epidermal cell membranes. The CDSN-deficient skin models were treated with liposomal CDSN and demonstrated the presence of the replaced protein within the granular layer. Finally, the skin barrier test and microscopy showed improved skin integrity (skin that functioned better), if the skin models were treated with liposomal CDSN. We believe that this study presents helpful laboratory results to develop a protein replacement therapy for patients with peeling skin syndrome and other diseases where there is also a lack of CDSN. Volume184, Issue6June 2021Pages e197-e197 RelatedInformation

Development of a pathogenesis-based therapy for peeling skin syndrome type 1.

Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory. The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated. The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN-deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN. This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.

Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A

Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers.

Counterregulation between thymic stromal lymphopoietin– and IL-23–driven immune axes shapes skin inflammation in mice with epidermal barrier defects

Epidermal barrier dysfunction has been recognized as a critical factor in the initiation and exacerbation of skin inflammation, particularly in patients with atopic dermatitis (AD) and AD-like congenital disorders, including peeling skin syndrome type B. However, inflammatory responses developed in barrier-defective skin, as well as the underlying mechanisms, remained incompletely understood. We aimed to decipher inflammatory axes and the cytokine network in mouse skin on breakdown of epidermal stratum corneum barrier. We generated Cdsn(iep-/-) mice with corneodesmosin ablation in keratinocytes selectively in an inducible manner. We characterized inflammatory responses and cytokine expression by using histology, immunohistochemistry, ELISA, and quantitative PCR. We combined mouse genetic tools, antibody-mediated neutralization, signal-blocking reagents, and topical antibiotic treatment to explore the inflammatory axes. We show that on breakdown of the epidermal stratum corneum barrier, type 2 and type 17 inflammatory responses are developed simultaneously, driven by thymic stromal lymphopoietin (TSLP) and IL-23, respectively. Importantly, we reveal a counterregulation between these 2 inflammatory axes. Furthermore, we show that protease-activated receptor 2 signaling is involved in mediating the TSLP/type 2 axis, whereas skin bacteria are engaged in induction of the IL-23/type 17 axis. Moreover, we find that IL-1β is induced in skin of Cdsn(iep-/-) mice and that blockade of IL-1 signaling suppresses both TSLP and IL-23 expression and ameliorates skin inflammation. The inflammatory phenotype in barrier-defective skin is shaped by counterregulation between the TSLP/type 2 and IL-23/type 17 axes. Targeting IL-1 signaling could be a promising therapeutic option for controlling skin inflammation in patients with peeling skin syndrome type B and other diseases related to epidermal barrier dysfunction, including AD.

Differential Diagnosis of Genetic Disorders Associated with Moderate to Severe Refractory Eczema and Elevated Immunoglobulin E

The association of moderate to severe eczema and elevated plasma levels of immunoglobulin E is a characteristic not only of atopic dermatitis but also of various genodermatoses: hyperimmunoglobulin E syndromes, Omenn syndrome, Netherton syndrome, peeling skin syndrome type B, severe dermatitis, multiple allergies, and metabolic wasting syndrome, Wiskott-Aldrich syndrome, prolidase deficiency, Loeys-Dietz syndrome, IPEX syndrome, STAT5B deficiency, and pentasomy X. The clinical presentation of these genodermatoses –typically in children– is consistent with severe atopic dermatitis. Immunoglobulin E is elevated from birth and response to conventional treatments is poor. Diagnosis is further complicated by the fact that these genodermatoses often share other clinical manifestations and laboratory findings. We present practical guidelines for differentiating among these various entities, with the aim of helping physicians decide what type of genetic test should be carried out –and when– in order to establish a definitive diagnosis.

Trastornos genéticos con eccema moderado-grave refractario y elevación de inmunoglobulina E: diagnóstico diferencial

The association of moderate to severe eczema and elevated plasma levels of immunoglobulin E is a characteristic not only of atopic dermatitis but also of various genodermatoses: hyperimmunoglobulin E syndromes, Omenn syndrome, Netherton syndrome, peeling skin syndrome type B, severe dermatitis, multiple allergies, and metabolic wasting syndrome, Wiskott-Aldrich syndrome, prolidase deficiency, Loeys-Dietz syndrome, IPEX syndrome, STAT5B deficiency, and pentasomy X. The clinical presentation of these genodermatoses –typically in children– is consistent with severe atopic dermatitis. Immunoglobulin E is elevated from birth and response to conventional treatments is poor. Diagnosis is further complicated by the fact that these genodermatoses often share other clinical manifestations and laboratory findings. We present practical guidelines for differentiating among these various entities, with the aim of helping physicians decide what type of genetic test should be carried out –and when– in order to establish a definitive diagnosis.

Peeling off the genetics of atopic dermatitis–like congenital disorders

The epidermis forms during the course of a complex differentiation process known as cornification, which culminates with the formation of the epidermal barrier. The epidermal barrier serves as a vital line of defense against the environment and mainly consists of 3 elements: intracellular keratin filaments, intercellular lipids, and the cornified cell envelope. Adequate epidermal barrier function is also critically dependent on normal shedding of terminally differentiated keratinocytes, a process termed desquamation, which requires the dissolution of cell-cell junctions in the upper granular layers. Although much has been learned about epidermal differentiation through the deciphering of the molecular basis of various cornification disorders, less is currently known about the mechanisms regulating epidermal desquamation and disorders resulting from disruption of this process. Netherton syndrome, peeling skin syndrome type B, and skin dermatitis--multiple severe allergies--metabolic wasting syndrome are 3 autosomal recessive conditions resulting from aberrant regulation of epidermal desquamation. The deciphering of their pathogenesis has not only broadened our understanding of this process but has also shed new light on clinical and mechanistic links between allergic reactions and abnormal desquamation, substantiating the notion that allergic manifestations might, under some circumstances, be the sole consequence of a primary epidermal defect.

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.

Identification of the first nonsenseCDSNmutation with expression of a truncated protein causing peeling skin syndrome type B

Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN). To investigate a novel mutation in CDSN. A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.

Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B)

BackgroundAtopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components’ localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. ObjectiveTo determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components’ distribution and corneocytes surface areas. MethodsCorneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. ResultsThe corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell–cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. ConclusionThis method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test.

Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome

Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A.

Peeling skin diseases: 21 cases from Turkey and a review of the literature

Peeling skin diseases (PSD) refer to a group of rare autosomal recessive dermatosis which are characterized by spontaneous, continual peeling of the skin. Three different clinical pictures can be distinguished: Inflammatory PSD also referred to as peeling skin syndrome (PSS) type B, non-inflammatory PSD also referred to as PSS type A, and localized forms i.e. acral type PSS. To characterize the clinical and histopathological features of PSD in Turkey. We retrospectively reviewed the medical records and clinical photographs of patients who were given diagnosis of PSD and conducted histopathological evaluation of skin biopsies to identify the site of cleavage. Also we evaluated the cases including age, gender, age onset, clinical and histological findings, family history, associated disorders and PSD type. Twenty-one patients with PSD were seen at Gulhane School of Medicine in Ankara between the years 1994 and 2010 in this retrospective study. All patients were men. Their ages were between 20 and 26 years (22.44±2.30, Mean age±SD). Of the patients, eight cases (40%) were type A, eight cases (40%) were type B, and five cases (20%) were acral type PSS. Eleven cases (52%) had parental consanguinity. Keratoderma, cheilitis, keratosis pilaris, melanonichia, clubbing, hyperhidrosis, onychodystrophy were observed in eight cases as an accompanying disorder. In this case series, PSD occurred rarely and also showed generally mild course of disease in Turkey and most likely related to consanguineous of marriages. Future investigations on PSD will contribute to our progressing alternative targets for pathogenesis-based therapy.

Comèl–Netherton syndrome and peeling skin syndrome type B: overlapping syndromes or one entity?

A 42-year-old male patient suffering from the rare Comèl-Netherton syndrome is reported, and the symptoms are discussed together with the results of light and electron microscopic examinations. Our case presented peeling skin syndrome type B with spontaneous, lifelong skin shedding with underlying erythema; however, with more careful studies, the hidden features of Comèl-Netherton syndrome were identified. This is an example of a condition where there is no clear border between Comèl-Netherton syndrome and peeling skin syndrome type B, lending credence to a close relationship between the two syndromes.

Comel-Netherton Syndrome: Evolution of Manifestation in a 20-year Follow-up and Phenotypic Overlap with Peeling Skin Syndrome Type B

Comel-Netherton Syndrome: Evolution of Manifestation in a 20-year Follow-up and Phenotypic Overlap with Peeling Skin Syndrome Type B