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BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets. OBJECTIVES: To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice. METHODS: Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-ß1 (TGF-ß1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice. RESULTS: Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-ß1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients. CONCLUSIONS: Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.
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Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-ß1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-ß1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.
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Secretasas de la Proteína Precursora del Amiloide , Epidermólisis Ampollosa Distrófica , Fibroblastos , Fibrosis , Proteína Jagged-1 , Transducción de Señal , Humanos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Epidermólisis Ampollosa Distrófica/tratamiento farmacológico , Epidermólisis Ampollosa Distrófica/patología , Epidermólisis Ampollosa Distrófica/genética , Transducción de Señal/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Regulación hacia Abajo/efectos de los fármacos , Receptor Notch1/metabolismo , Receptor Notch1/antagonistas & inhibidores , Receptor Notch1/genética , Dipéptidos/farmacología , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Células Cultivadas , Piel/patología , Piel/efectos de los fármacos , Piel/metabolismo , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Femenino , Diaminas , Tetrahidronaftalenos , Tiazoles , Valina/análogos & derivadosRESUMEN
Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.
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(1) Background: Atopic dermatitis constitutes one of the most common inflammatory skin manifestations of the pediatric population. The onset of many inborn errors occurs early in life with an AD-like picture associated with a deregulated IgE response. The availability of proteomic tests for the simultaneous evaluation of hundreds of molecules allows for more precise diagnosis in these cases. (2) Methods: Comparative genomic hybridization microarray (Array-CGH) analysis and specific IgE evaluation by using allergenic microarray (ISAC) and microarray (ALEX2) systems were performed. (3) Results: Proteomic investigations that use multiplex methods have proven to be extremely useful to diagnose the sensitization profile in inborn errors with deregulated IgE synthesis. Four patients with rare diseases, such as recessive X-linked ichthyosis (RXLI, OMIM 308100), Comel-Netherton syndrome (NS, OMIM256500), monosomy 1p36 syndrome (OMIM: 607872), and a microduplication of Xp11.4 associated with extremely high levels of IgE: 7.710 kU/L, 5.300 kU/L, 1.826 kU/L, and 10.430 kU/L, respectively, were evaluated by micro- and macroarray multiplex methods. Polyreactivity to both environmental and food allergens was observed in all cases, including the first described case of association of X-chromosome microduplication and HIE. (4) Conclusions: Extensive use of proteomic diagnostics should be included among the procedures to be implemented in inborn errors with hyper-IgE.
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Ictiosis , Fotofobia , Humanos , Ictiosis/complicaciones , Ictiosis/diagnóstico , Alopecia/diagnóstico , MetaloendopeptidasasRESUMEN
BACKGROUND: Scant data are currently available on the allergen-specific immunoglobulin (Ig)E sensitization profile in primary immunodeficiencies with hyper IgE. Netherton syndrome (NS, OMIM 266500) is an extremely rare form of congenital ichthyosis characterized by congenital scaly erythroderma, hair abnormalities, and deregulated IgE reactivity associated with severe atopic manifestations. OBJECTIVE: The aim of this study was to evaluate the feasibility and reliability of a multiplex proteomic approach in the detection of specific IgE in NS. METHODS: Specific IgE was evaluated in 10 individuals with an established molecular diagnosis of NS using an allergenic molecules microarray (immuno-solid-phase allergen chip). RESULTS: Polireactivity to airway allergens, mainly house dust mites and olive tree pollen, and food allergens were observed in NS. Eighty per cent of patients were responsive to LTP or profilins. A clinical history suggestive of severe egg, milk, and fish allergy was confirmed by reactivity to the thermostable molecules Gal d 1, Bod 8, and parvalbumin Gad c 1, respectively. Latex reactivity was associated with Hev b 5 and 6 reactivity. Two distinct clusters of reactivity were observed after hierarchical analysis. Extremely high IgE levels (> 10,000 kU/L) do not affect the results obtained with microarrays. CONCLUSION: IgE multiplex evaluation allows (i) to profile IgE polyreactivity pictures, in the presence of LTP and profilin sensitization, (ii) to verify the clinical history of food allergy to milk, egg, and seafood, (iii) to confirm the allergic events associated with latex exposure, and (iv) to disclose the presence of preclinical sensitizations in patients affected by primary immunodeficiencies with hyper IgE, such as the NS.
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Hipersensibilidad a los Alimentos , Síndrome de Netherton , Animales , Látex , Síndrome de Netherton/diagnóstico , Proteómica , Reproducibilidad de los Resultados , Reacciones Cruzadas , Inmunoglobulina E , Alérgenos , Profilinas , Hipersensibilidad a los Alimentos/diagnósticoRESUMEN
Autoimmune response to cutaneous basement membrane components superimposed on a genetic skin fragility disease, hereditary epidermolysis bullosa (EB), has been described, but its effects on disease course remain unclear. We report a 69-year-old individual with congenital skin fragility and acral trauma-induced blistering that had suddenly worsened with the onset of severe itch and diffuse spontaneous inflammatory blisters. Next-generation sequencing identified compound heterozygous null and missense COL7A1 mutations, allowing the diagnosis of recessive dystrophic EB. However, the patient's clinical history prompted us to investigate whether he might have developed a pathological autoimmune response against basement membrane components. Tissue-bound and circulating IgG antibodies to the major bullous pemphigoid (BP) antigen, BP180, were detected in the patient's skin and serum, respectively, consistent with a diagnosis of BP. Corticosteroid therapy was initiated resulting in remission of BP manifestations. EB patients presenting rapid disease worsening should be investigated for the development of a concomitant autoimmune blistering disease.
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Enfermedades Autoinmunes , Epidermólisis Ampollosa Distrófica , Penfigoide Ampolloso , Anciano , Enfermedades Autoinmunes/patología , Vesícula/patología , Colágeno/genética , Colágeno Tipo VII/genética , Epidermólisis Ampollosa Distrófica/complicaciones , Epidermólisis Ampollosa Distrófica/diagnóstico , Epidermólisis Ampollosa Distrófica/genética , Humanos , Masculino , Penfigoide Ampolloso/diagnóstico , Penfigoide Ampolloso/tratamiento farmacológico , PielRESUMEN
BACKGROUND: Secreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations. Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization of RSPO1-mutated skin and keratinocytes. RESULTS: Cultured primary keratinocytes from PPK skin of a RSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly, RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell-cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient's keratinocytes exhibited increased expression of cellâmatrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably, RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens of RSPO1-mutated patient compared to control. CONCLUSIONS: Altogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.
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Carcinoma de Células Escamosas , Queratodermia Palmoplantar , Neoplasias Cutáneas , Carcinoma de Células Escamosas/metabolismo , Adhesión Celular/genética , Transición Epitelial-Mesenquimal/genética , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratodermia Palmoplantar/genética , Queratodermia Palmoplantar/patología , Fenotipo , Desarrollo Sexual , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Trombospondinas/genética , Trombospondinas/metabolismo , Microambiente TumoralRESUMEN
Multiple intestinal atresia with combined immune deficiency (MIA-CID) is an autosomal recessive syndrome due to mutations in the TTC7A gene implicated in the polarization of intestinal and thymic epithelial cells. MIA-CID is lethal in the first year of life in the majority of patients. Dermatological manifestations have been reported in a few cases. We describe a child affected with MIA-CID due to a previously unreported TTC7A homozygous missense mutation. Surgery for bowel occlusion was performed in the first days of life. The patient was totally dependent on parenteral nutrition since birth and presented severe diarrhea and recurrent infections. He underwent hematopoietic stem cell transplantation at 17 months with complete donor engraftment and partial immunity improvement. In the second year of life, he progressively developed diffuse papular follicular keratoses on ichthyosiform skin, nail clubbing, and subungual hyperkeratosis. Histopathology showed hyperkeratosis with follicular plugging and scattered apoptotic keratinocytes, visualized at an ultrastructural examination. Our findings expand the spectrum of dermatological manifestations which can develop in MIA-CID patients. Examination of further patients will allow defining whether keratinocyte apoptosis is also a disease feature.
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Enfermedad de Darier , Atresia Intestinal , Enfermedades de Inmunodeficiencia Primaria , Anomalías Múltiples , Niño , Cejas/anomalías , Humanos , Atresia Intestinal/genética , Atresia Intestinal/patología , Masculino , Mutación , Proteínas/genéticaRESUMEN
Epidermal development and maintenance are finely regulated events requiring a strict balance between proliferation and differentiation. Alterations in these processes give rise to human disorders such as cancer or syndromes with skin and annexes defects, known as ectodermal dysplasias (EDs). Here, we studied the functional effects of two novel receptor-interacting protein kinase 4 (RIPK4) missense mutations identified in siblings with an autosomal recessive ED with cutaneous syndactyly, palmoplantar hyperkeratosis and orofacial synechiae. Clinical overlap with distinct EDs caused by mutations in transcription factors (i.e. p63 and interferon regulatory factor 6, IRF6) or nectin adhesion molecules was noticed. Impaired activity of the RIPK4 kinase resulted both in altered epithelial differentiation and defective cell adhesion. We showed that mutant RIPK4 resulted in loss of PVRL4/nectin-4 expression in patient epidermis and primary keratinocytes, and demonstrated that PVRL4 is transcriptionally regulated by IRF6, a RIPK4 phosphorylation target. In addition, defective RIPK4 altered desmosome morphology through modulation of plakophilin-1 and desmoplakin. In conclusion, this work implicates RIPK4 kinase function in the p63-IRF6 regulatory loop that controls the proliferation/differentiation switch and cell adhesion, with implications in ectodermal development and cancer.
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Displasia Ectodérmica , Factores Reguladores del Interferón , Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Displasia Ectodérmica/metabolismo , Homeostasis , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Queratinocitos/metabolismo , Nectinas , Proteínas Serina-Treonina QuinasasRESUMEN
BACKGROUND: Autosomal recessive congenital ichthyoses (ARCI) are a genetically heterogeneous group of rare and chronic disorders characterized by generalized skin scaling and hyperkeratosis, erythroderma, and palmoplantar keratoderma. Additional features include ectropion, eclabium, ear deformities, foul-smell, joints contractures and walking problems, recurrent infections, as well as pruritus and pain. No curative therapy is available and disease care mainly relies on daily application of topical emollients and keratolytics to the whole-body surface. Altogether, disease signs and symptoms and treatment modalities have a major impact on quality of life of patients and their caregivers. However, very few studies have evaluated the family disease burden in ARCI. METHODS: We have performed an Italian multicenter cross-sectional study to assess the secondary disease impact on family members of pediatric and adult patients with ARCI, using a validated dermatology-specific questionnaire, the family dermatology life quality index (FDLQI). Disease severity was assessed by the dermatologist in each center. RESULTS: Seventy-eight out of 82 patients who were accompanied by at least one family member filled the FDLQI. Forty-eight (61.5%) patients were aged less than 18 years. The mean FDLQI score was 10.3 (median 10), and the most affected dimensions were (1) time needed for care, (2) extra-housework, and (3) household expenditure. Higher total FDLQI score significantly correlated with more severe disease score (P = 0.003). Features associated with greater family burden included recurrent infections (P = 0.004), foul-smell (P = 0.009), palmoplantar keratoderma (P = 0.041), but also presence of scales on the face (P = 0.039) and ear deformities (P = 0.016). CONCLUSIONS: Our findings highlight the major socio-economic and psychological burden imposed by ARCI on the QoL of family caregivers. In addition, they show that global evaluation of disease impact also on family members is an essential part of patient-reported outcomes. Finally, our data underline the need to develop specific measures for family support.
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Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Queratodermia Palmoplantar , Adulto , Niño , Estudios Transversales , Humanos , Calidad de VidaRESUMEN
R-spondin (RSPO)1 is a fibroblast-secreted protein that belongs to the R-spondin protein family which is essential for reproductive organ development, epithelial stem cell renewal and cancer induction or suppression. RSPO1 gene mutations cause palmoplantar hyperkeratosis with squamous cell carcinoma (SCC) of the skin, 46XX sex reversal and true hermaphroditism. To characterize RSPO1-deficient skin fibroblasts derived from two patients with mutations in RSPO1, with palmoplantar hyperkeratosis, recurrent SCC and 46XX sex reversal, to provide further insight into disease-related skin tumourigenesis. Fibroblast cultures from non-tumoural palmoplantar skin biopsies were established to evaluate features and properties that may be altered at cancer onset, i.e. proliferation, extracellular matrix contraction and invasion, as well as TGF-ß and matrix metalloproteinase (MMP) secretion. Fibroblasts demonstrated increased proliferative potential in vitro, a high level of collagen contraction and invasion by SCC cells, release of high levels of pro-inflammatory and pro-fibrotic TGF-ß, and increased expression of MMP1 and MMP3. Analysis of the expression of selected proteins associated with RSPO1-activated pathways confirmed sustained activation of the TGF-ß signalling pathway and indicated a loss of TGF-ß inhibitory feedback. Also, treatment of fibroblasts with a recombinant RSPO1 protein aggravated this pro-inflammatory phenotype, suggesting caution in designing therapeutic strategies based on restoration of protein function. Our findings indicate that fibroblasts from RSPO1-mutated patients behave similarly to cancer-associated fibroblasts. Chronic inflammation and fibrotic changes in palmoplantar skin may play a role in SCC development and recurrence, possibly by irreversibly activating the tumourigenic phenotype of fibroblasts.
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Fibroblastos/patología , Queratodermia Palmoplantar/patología , Mutación , Trombospondinas/genética , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Masculino , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Fenotipo , Transducción de Señal , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.
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Distrofias Hereditarias de la Córnea/genética , Epidermólisis Ampollosa de la Unión/genética , Epitelio Corneal/patología , Soluciones Oftálmicas/uso terapéutico , Fenotipo , Amnios/química , Adhesión Celular , Moléculas de Adhesión Celular/genética , Células Cultivadas , Preescolar , Distrofias Hereditarias de la Córnea/tratamiento farmacológico , Distrofias Hereditarias de la Córnea/patología , Epidermólisis Ampollosa de la Unión/tratamiento farmacológico , Epidermólisis Ampollosa de la Unión/patología , Femenino , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Queratinocitos/fisiología , Mutación , Soluciones Oftálmicas/química , Soluciones Oftálmicas/farmacología , Piel/patología , KalininaRESUMEN
Fibrosis can be defined as an excessive and deregulated deposition of extracellular matrix proteins, causing loss of physiological architecture and dysfunction of different tissues and organs. In the skin, fibrosis represents the hallmark of several acquired (e.g. systemic sclerosis and hypertrophic scars) and inherited (i.e. dystrophic epidermolysis bullosa) diseases. A complex series of interactions among a variety of cellular types and a wide range of molecular players drive the fibrogenic process, often in a context-dependent manner. However, the pathogenetic mechanisms leading to skin fibrosis are not completely elucidated. In this scenario, an increasing body of evidence has recently disclosed the involvement of Notch signalling cascade in fibrosis of the skin and other organs. Despite its apparent simplicity, Notch represents one of the most multifaceted, strictly regulated and intricate pathways with still unknown features both in health and disease conditions. Starting from the most recent advances in Notch activation and regulation, this review focuses on the pro-fibrotic function of Notch pathway in fibroproliferative skin disorders describing molecular networks, interplay with other pro-fibrotic molecules and pathways, including the transforming growth factor-ß1, and therapeutic strategies under development.
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Cicatriz Hipertrófica/genética , Fibrosis/genética , Receptores Notch/metabolismo , Esclerodermia Sistémica/genética , Transducción de Señal , Cicatriz Hipertrófica/patología , Fibrosis/patología , Esclerodermia Sistémica/patología , Piel/patologíaRESUMEN
Autosomal recessive congenital ichthyoses (ARCI) are characterized by generalized skin scaling, hyperkeratosis, erythroderma, and disabling features affecting the skin (palmoplantar keratoderma, fissures, pain, itch), eyes, ears, and joints. Disease severity and chronicity, patient disfigurement, and time and costs required for care impose a major burden on quality of life. This multicentre cross-sectional study investigated the impact of ARCI on quality of life of patients and families, using the Dermatology Life Quality Index (DLQI), the Children DLQI (CDLQI) and Family Burden of Ichthyosis (FBI) questionnaires. Disease severity was assessed by a dermatologist. A total of 94 patients were recruited, of whom 52 (55.3%) children. Mean age was 20.1 (median 13.5) years. The mean CDLQI/DLQI score was 7.8, and 21 patients scored >10, indicating a major impairment in quality of life: symptoms, feelings and treatment problems were the most affected domains of quality of life. FBI showed a major repercussion on psychological factors and work. The results of this study highlight the impact of ARCI on specific aspects of patient and family life, underlining the need for psychological support.
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Eritrodermia Ictiosiforme Congénita , Ictiosis Lamelar , Ictiosis , Adulto , Niño , Estudios Transversales , Humanos , Eritrodermia Ictiosiforme Congénita/diagnóstico , Eritrodermia Ictiosiforme Congénita/epidemiología , Eritrodermia Ictiosiforme Congénita/genética , Ictiosis/diagnóstico , Ictiosis/epidemiología , Ictiosis/genética , Ictiosis Lamelar/diagnóstico , Ictiosis Lamelar/genética , Ictiosis Lamelar/terapia , Italia/epidemiología , Calidad de Vida , Adulto JovenRESUMEN
Keratinopathic ichthyoses (KI) are a clinically heterogeneous group of keratinization disorders due to mutations in KRT1, KTR10, or KRT2 genes encoding keratins of suprabasal epidermis. Characteristic clinical features include superficial blisters and erosions in infancy and progressive development of hyperkeratosis. Histopathology shows epidermolytic hyperkeratosis. We describe the clinical, histopathological, and molecular findings of a series of 26 Italian patients from 19 unrelated families affected with (i) epidermolytic ichthyosis due to KRT1 or KRT10 mutations (7 and 9 cases, respectively); (ii) KTR10-mutated ichthyosis with confetti (2 cases); (iii) KRT2-mutated superficial epidermolytic ichthyosis (5 cases); and (iv) KRT10-mutated epidermolytic nevus (2 cases). Of note, molecular genetic testing in a third case of extensive epidermolytic nevus revealed a somatic missense mutation (p.Asn186Asp) in the KRT2 gene, detected in DNA from lesional skin at an allelic frequency of 25% and, at very low frequency (1.5%), also in blood. Finally, we report three novel dominant mutations, including a frameshift mutation altering the C-terminal V2 domain of keratin 1 in three familiar cases presenting a mild phenotype. Overall, our findings expand the phenotypic and molecular spectrum of KI and show for the first time that epidermolytic nevus can be due to somatic KRT2 mutation.
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Hiperqueratosis Epidermolítica/genética , Queratina-2/genética , Nevo/genética , Adulto , Secuencia de Bases , Niño , Preescolar , Femenino , Humanos , Hiperqueratosis Epidermolítica/patología , Lactante , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Piel/patología , Piel/ultraestructura , Adulto JovenRESUMEN
Variably reduced expression of the basement membrane component laminin-332 (α3aß3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a ß3 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to γ2 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient.
Asunto(s)
Carcinoma de Células Escamosas , Moléculas de Adhesión Celular , Epidermólisis Ampollosa , Mutación , Proteínas de Neoplasias , Neoplasias Cutáneas , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa/metabolismo , Epidermólisis Ampollosa/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , KalininaRESUMEN
Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.
Asunto(s)
Carcinoma de Células Escamosas/etiología , Susceptibilidad a Enfermedades , Epidermólisis Ampollosa/complicaciones , Animales , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Manejo de la Enfermedad , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa/metabolismo , Humanos , Vigilancia de la Población , Transducción de Señal , Microambiente Tumoral , Cicatrización de HeridasAsunto(s)
Conexinas/genética , Pérdida Auditiva Sensorineural/genética , Queratodermia Palmoplantar/genética , Mutación , Polimorfismo de Nucleótido Simple , Piel/patología , Adulto , Conexina 26 , Femenino , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/patología , Humanos , Queratodermia Palmoplantar/patología , Fenotipo , SíndromeRESUMEN
Hereditary spherocytosis is the most common inherited hemolytic anemia characterized by the presence of spherical-shaped erythrocytes on peripheral blood smear. The clinical manifestations of HS are highly variable, from severe forms to asymptomatic forms. HS is caused by defects in red blood cell membrane proteins, encoded by the ANK1, EPB42, SLC4A1, SPTA1 and SPTB genes. Mutation of the ANK 1 gene is the most common and inheritance is autosomal dominant in 75% of cases. In our case, heterozygous an ANK1 c.4123C > T mutation was identified in a 4-year-old girl, using targeted next-generation sequencing and Sanger sequencing.