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1.
Exp Dermatol ; 33(3): e15046, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38509711

RESUMO

Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.


Assuntos
Desmoplaquinas , Receptores ErbB , Doenças do Cabelo , Ceratodermia Palmar e Plantar , Humanos , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Epiderme/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Doenças do Cabelo/genética , Queratinócitos/metabolismo , Ceratodermia Palmar e Plantar/genética , Fenótipo , Pele/metabolismo
2.
Cell Mol Life Sci ; 81(1): 102, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38409522

RESUMO

The protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a non-canonical, phosphorylation-independent 14-3-3 interaction site that encompasses all known TOC mutations. Disruption of this site dysregulates ADAM17 activity. The larger cub deletion also includes the TOC site and thus also dysregulated ADAM17 activity. The cub deletion, but not the TOC mutation, also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, demonstrating the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences, and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17.


Assuntos
Proteínas de Transporte , Neoplasias Esofágicas , Ceratodermia Palmar e Plantar , Humanos , Camundongos , Animais , Fosforilação , Proteínas de Transporte/metabolismo , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Transdução de Sinais/genética , Mutação , Neoplasias Esofágicas/genética
4.
Pediatr Dermatol ; 41(2): 369-371, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38165066

RESUMO

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive form of diffuse palmoplantar keratoderma (PPK) characterized by thickening and redness of palms and/or soles. In this report, we describe a female patient of Korean descent who had clinical remission of her adult-onset NPPK. To our knowledge, she is the first reported heterozygous SERBINB7 mutation carrier to present with classic NPPK who achieved spontaneous clinical remission.


Assuntos
Ceratodermia Palmar e Plantar , Serpinas , Adulto , Humanos , Feminino , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Serpinas/genética , Mutação , Povo Asiático/genética , República da Coreia
5.
J Invest Dermatol ; 144(2): 284-295.e16, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37716648

RESUMO

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.


Assuntos
Doenças do Cabelo , Ceratodermia Palmar e Plantar , Anormalidades da Pele , Animais , Humanos , Camundongos , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Desmossomos/metabolismo , Cabelo/metabolismo , Doenças do Cabelo/genética , Doenças do Cabelo/metabolismo , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/metabolismo , Pele/metabolismo , Anormalidades da Pele/metabolismo
6.
JAMA Dermatol ; 160(2): 218-219, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38055272

RESUMO

This case report describes a 6-year-old girl who presented with symmetrical massive keratotic plaques on the palms, soles, and perioral area, as well as hair loss for 4 years.


Assuntos
Ceratodermia Palmar e Plantar , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Pele
9.
J Eur Acad Dermatol Venereol ; 38(2): 413-418, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37684051

RESUMO

BACKGROUND: Hereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss-of-function variants in a serine peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima-type PPK (NPPK) caused by biallelic variants in SERPINB7. OBJECTIVES: The aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease-related hPPKs caused by variants in SERPINA12 and SERPINB7. METHODS: Whole-exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12- and SERPINB7-related hPPKs was summarized. RESULTS: The phenotype of SERPINA12-related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non-palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis. CONCLUSIONS: Recessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non-Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.


Assuntos
Hiperidrose , Ceratodermia Palmar e Plantar , Serpinas , Humanos , Pré-Escolar , Mutação , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Mutação de Sentido Incorreto , Peptídeo Hidrolases/genética , Serpinas/genética
10.
J Invest Dermatol ; 144(4): 748-754, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38099888

RESUMO

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.


Assuntos
Ceratodermia Palmar e Plantar , Paquioníquia Congênita , Humanos , Paquioníquia Congênita/diagnóstico , Paquioníquia Congênita/genética , Paquioníquia Congênita/terapia , Ceratodermia Palmar e Plantar/genética , Administração Cutânea , Apoptose , Diferenciação Celular , Mutação
11.
Dermatol Online J ; 29(4)2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37921818

RESUMO

Spiny keratoderma is a rare skin condition that presents on the palmar and plantar surfaces of the hands and/or feet. This condition is difficult to appreciate under ambient lighting but can be both physically and emotionally distressing to patients. Furthermore, because of the association with various neoplasms and systemic diseases, timely diagnosis and appropriate follow-up is of importance. We evaluate a case of spiny keratoderma in a patient with recently diagnosed hypothyroidism and emphasize the importance of proper lighting during a dermatology-focused physical examination. The patient's palmar lesions were only appreciable under LED light and with physical examination. A biopsy of the lesions confirmed the diagnosis of spiny keratoderma.


Assuntos
Ceratodermia Palmar e Plantar , Neoplasias , Doenças da Glândula Tireoide , Humanos , Ceratodermia Palmar e Plantar/etiologia , Ceratodermia Palmar e Plantar/complicações , Pele/patologia , Neoplasias/complicações
13.
15.
Orphanet J Rare Dis ; 18(1): 290, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37705065

RESUMO

BACKGROUND: An association between punctate palmoplantar keratoderma type 1 (PPPK1) and malignancy has been proposed for decades. Some authors suggest that individuals with PPPK1 should undergo screening for various types of malignancies while others caution that an association is not well-established. In this systematic review, we summarized and evaluated the current evidence for a possible association between PPPK1 and malignancy. METHODS: The review was conducted along PRISMA guidelines. The search used Embase, MEDLINE, Scopus, and the Human Gene Mutation Database up to March 2022. All studies reporting on individuals with the diagnosis of PPPK1 with or without history of malignancy were included. Two authors screened for eligible studies, extracted predefined data, and performed a quality assessment. RESULTS: Of 773 studies identified, 45 were included. Most studies were reports on single families (24 of 45 studies) or multiple families (10 of 45 studies). The number of index cases with PPPK1 across all included studies was 280, and when family members reported with PPPK1 were added, a total of 817 individuals were identified. Overall, 23 studies reported on individuals with PPPK1 with a history of malignancy, whereas 22 studies reported on individuals with PPPK1 without a history of malignancy. Although the extracted data were not considered to be of sufficient quality to synthesize and answer our research question, the review did not confirm an association between PPPK1 and malignancy. CONCLUSION: This review shows that there is a lack of well-designed studies on this topic to conclude whether individuals with PPPK1 have an increased risk of malignancy. Based on the present literature, however, we could not confirm an association between PPPK1 and malignancy and find it highly questionable if patients with PPPK1 should be offered surveillance for malignancies.


Assuntos
Ceratodermia Palmar e Plantar , Neoplasias , Humanos , Neoplasias/genética , Ceratodermia Palmar e Plantar/genética , Bases de Dados Factuais , Família
16.
Int J Mol Sci ; 24(18)2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37762265

RESUMO

Ichthyoses are genetically determined cornification disorders of the epidermis characterized by the presence of different degrees of scaling, hyperkeratosis, and erythroderma often associated with palmoplantar keratoderma. Different classifications of these diseases have been proposed, often based upon the involved genes and/or the clinical presentation. The clinical features of these diseases present some overlap of phenotypes among distinct genetic entities, depending mainly on the penetrance of mutations. In this study, using a clinical, genetic, and molecular approach, we analyzed a family with two affected members who had clinical and histological features resembling erythrokeratodermia variabilis (EKV) or a type of erythrodermic hyperkeratosis with palmoplantar keratoderma. Despite of the clinical presentation, we demonstrated that the affected patients were genetically double heterozygous for two different mutations in the ABCA12 gene, known to be responsible for harlequin ichthyosis. To explain the mild phenotype of our patients, we performed a molecular characterization of the skin. In the upper layers of the epidermis, the results showed a patchy presence of the glucosyl-ceramides (GlcCer), which is the lipid transported by ABCA12, fundamental in contributing to skin impermeability. Indeed, the two mutations detected do not completely abolish ABCA12 activity, indicating that the mild phenotype is due to a partial loss of function of the enzyme, thus giving rise to an intermediate phenotype resembling EKVP, due to a partial depletion of GlcCer deposition.


Assuntos
Eritroceratodermia Variável , Ictiose Lamelar , Ictiose , Ceratodermia Palmar e Plantar , Humanos , Eritroceratodermia Variável/genética , Ictiose Lamelar/genética , Ictiose/genética , Mutação , Glucosilceramidas , Transportadores de Cassetes de Ligação de ATP/genética
17.
J Cutan Med Surg ; 27(6): 673, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37594004
18.
Dermatol Online J ; 29(3)2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37591271

RESUMO

Spiny keratoderma (SKD) is a rare palmoplantar keratoderma that presents with few to numerous millimetric hyperkeratotic projections on the palms and soles. It has been described with both hereditary and acquired variants. The acquired form, which presents in older adults, has been associated with a variety of systemic diseases and malignant conditions. In patients suspected of having acquired spiny keratoderma, an evaluation for malignant conditions may be warranted. Treatment with topical keratolytics or topical and oral retinoids is usually insufficient. Herein, we present the case of a 58-year-old man diagnosed with idiopathic SKD.


Assuntos
Ceratodermia Palmar e Plantar , Masculino , Humanos , Idoso , Pessoa de Meia-Idade , Ceratodermia Palmar e Plantar/diagnóstico , Retinoides , Síndrome
19.
BMC Med Genomics ; 16(1): 152, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37393290

RESUMO

BACKGROUND: Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family. METHODS: We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis. RESULTS: Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL. CONCLUSIONS: Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.


Assuntos
Antígenos Ly , População do Leste Asiático , Ceratodermia Palmar e Plantar , Ativador de Plasminogênio Tipo Uroquinase , Adulto , Feminino , Humanos , Algoritmos , Antígenos Ly/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Ativador de Plasminogênio Tipo Uroquinase/genética
20.
Sci Rep ; 13(1): 11463, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37454166

RESUMO

This paper introduces superpixels to enhance the detection of skin lesions and to discriminate between melanoma and nevi without false negatives, in dermoscopy images. An improved Simple Linear Iterative Clustering (iSLIC) superpixels algorithm for image segmentation in digital image processing is proposed. The local graph cut method to identify the region of interest (i.e., either the nevi or melanoma lesions) has been adopted. The iSLIC algorithm is then exploited to segment sSPs. iSLIC discards all the SPs belonging to image background based on assigned labels and preserves the segmented skin lesions. A shape and geometric feature extraction task is performed for each segmented SP. The extracted features are fed into six machine learning algorithms such as: random forest, support vector machines, AdaBoost, k-nearest neighbor, decision trees (DT), Gaussian Naïve Bayes and three neural networks. These include Pattern recognition neural network, Feed forward neural network, and 1D Convolutional Neural Network for classification. The method is evaluated on the 7-Point MED-NODE and PAD-UFES-20 datasets and the results have been compared to the state-of-art findings. Extensive experiments show that the proposed method outperforms the compared existing methods in terms of accuracy.


Assuntos
Ceratodermia Palmar e Plantar , Melanoma , Nevo , Neoplasias Cutâneas , Humanos , Teorema de Bayes , Melanoma/diagnóstico por imagem , Melanoma/patologia , Algoritmos , Nevo/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia
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