RESUMO
Transforming growth factor ß (TGF-ß) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-ß results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-ß signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient's fibroblasts were employed. We hypothesized an impairment of TGF-ß signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient's fibroblasts to losartan led to the partial restoration of normal transforming growth factor ß (TGF-ß) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-ß signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-ß signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.
Assuntos
Contratura/patologia , Transdução de Sinais , Dermatopatias Genéticas/patologia , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Adolescente , Contratura/diagnóstico por imagem , Contratura/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Imageamento por Ressonância Magnética , Fosforilação , Pele/diagnóstico por imagem , Pele/metabolismo , Dermatopatias Genéticas/diagnóstico por imagem , Dermatopatias Genéticas/metabolismoRESUMO
RATIONALE: Epidermolysis bullosa (EB) is an inherited disease characterized by fragile skin with painful blistering, which requires lifelong skin and wound care. This case report describes the use of inhaled nitrous oxide (N2O) for procedural pain control at home during wound care in a young man with severe dystrophic EB. To our knowledge, only 1 case was reported by Ingelmo et al in 2017 regarding the use of N2O at home in a 4-year-old-child. To date, no such attempt has been made in adult patients. PATIENT CONCERNS: Our patient was a 28-year-old man. Frequent blisters appear spontaneously, and are often preceded by erythema and itching. Patient required daily treatment daily consisting of lancing blisters with a needle and emptying them by compression. DIAGNOSES: Severe recessive dystrophic EB diagnosed at the time of delivery. INTERVENTIONS: Procedural pain control was managed by the auto-administration of an inhaled N2O and air gas mixture. OUTCOMES: Conscious sedation with N2O leads to beneficial effects, such as reduction in dressing duration, acute procedural pain, local antibiotic needing, medication memory, anxiety, anticipatory pain, and fatigue after the dressing session. LESSONS: N2O analgesia is safe and effective, resulting in a significant reduction in procedural pain and an improvement in the quality of life of patients and their caregivers.
Assuntos
Analgesia , Anestésicos Inalatórios/administração & dosagem , Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa/complicações , Epidermólise Bolhosa/terapia , Óxido Nitroso/administração & dosagem , Manejo da Dor/métodos , Dor Processual/prevenção & controle , Adulto , Analgesia/efeitos adversos , Analgesia/métodos , Anestésicos Inalatórios/farmacologia , Vesícula/etiologia , Vesícula/terapia , Humanos , Masculino , Óxido Nitroso/farmacologia , Dor , Qualidade de VidaAssuntos
Anticorpos Monoclonais/uso terapêutico , Epidermólise Bolhosa Distrófica/tratamento farmacológico , Imunossupressores/uso terapêutico , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Anticorpos Monoclonais Humanizados , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/diagnóstico , Epidermólise Bolhosa Distrófica/genética , Genes Recessivos , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Fenótipo , Recidiva , Pele/patologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The aim of our study was to provide a psychosocial and psychiatric evaluation of patients with epidermolysis bullosa (EB; a rare genetic disorder characterized by skin fragility), to assess psychological status, ascertain the presence of any psychiatric disorders and understand the impact of EB on quality of life. Twenty-five patients were assessed using a case record form and several standardized instruments. In 82% of patients, EB had a negative impact on quality of life and 80% of patients experienced psychiatric symptoms. Our findings revealed a high prevalence of psychosocial problems and psychiatric symptoms in patients with EB and suggested that a combined bio-psychosocial approach is the most appropriate therapeutic intervention.
Assuntos
Epidermólise Bolhosa/epidemiologia , Epidermólise Bolhosa/psicologia , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Entrevista Psicológica/métodos , Itália/epidemiologia , Masculino , Prevalência , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
INTRODUCTION: Mid-Aortic Syndrome (MAS) is a rare vascular malformation characterized by segmental narrowing of the abdominal aorta and stenosis of its principal branches. Patients affected by MAS typically present malignant renovascular hypertension, with variable clinical symptoms like claudication, abdominal angina, and headache. Moreover, they can develop other complications, such as hypertensive encephalopathy, congestive heart failure and vascular brain accidents. Hypertension with MAS is often resistant to multidrug therapy, requiring a surgical approach to treat the clinical symptoms, prevent or block organ damage and normalize the blood pressure. CASE REPORT: Here, the case of a 4-year-old boy showing elevated blood pressure with left ventricular hypertrophy leading to idiopathic MAS, who was successfully treated with percutaneous transcatheter renal angioplasty (PTRA) using an unusual, anterograde access, is reported. DISCUSSION AND CONCLUSION: In children and adolescents, vascular malformations like MAS must be considered as a possible cause of hypertension. PTRA is a successful therapeutic strategy in children with severe renovascular hypertension. Anterograde access, using an axillary artery, can be a valid approach for PTRA when femoral access is difficult to achieve.
Assuntos
Hipertensão Renovascular , Adolescente , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/cirurgia , Criança , Pré-Escolar , Quimioterapia Combinada , Humanos , Hipertensão Renovascular/diagnóstico , Hipertensão Renovascular/etiologia , Hipertensão Renovascular/terapia , Hansenostáticos , Masculino , SíndromeRESUMO
Epidermolysis bullosa (EB) is a rare disorder characterized by inherited skin adhesion defects with abnormal disruption of the epidermal-dermal junction in response to mechanical trauma. Our aim was to investigate a set of cytokine levels in serum samples from patients suffering from epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and healthy controls (HCs), exploring their potential correlations with antiskin autoantibody titers and disease activity. Forty patients afferent to the Dermatological Ward of Bari City Hospital and 9 HCs were enrolled and subdivided according to the dystrophic (DEB) and simplex forms (EBS). We found a significant increase in interleukin (IL)-1ß plasmatic levels of DEB (P = 0.0224) and EBS (P = 0.0465) patients compared to HCs; IL-6 levels were significantly higher in DEB than in EBS patients (P = 0.0004) or HCs (P = 0.0474); IL-2 levels were significantly increased in DEB compared with EBS (P = 0.0428). Plasmatic tumor necrosis factor-ß and interferon-γ were higher in DEB patients than in HCs (P = 0.0448 and 0.0229). Conversely, tumor necrosis factor-α was significantly decreased in DEB (P = 0.0034). IL-5 correlated with anti-BP180 (r =â-0.5018, P = 0.0338), anti-BP230 (r =â-0.6097, P = 0.0122), and anticollagen VII (r =â-0.5166, P = 0.0405) autoantibodies; interferon-γ correlated with anti-BP180 (r = 0.9633, P < 0.0001), anti-BP230 (r = 0.9071, P < 0.0001), and anticollagen VII (r = 0.8619, P = 0.0045) autoantibodies. Score of disease severity was significantly correlated with IL-6 (r = 0.6941, P = 0.029) and IL-12 (r = 0.5503, P = 0.0272). The present study supports that EB might be considered a systemic inflammatory disease rather than a skin-limited disorder; clinical disease activity scores could be also integrated by laboratory data such as IL-6 and IL-12 dosage; biotherapies targeting specific cytokine networks probably represent a way to go in the future.
Assuntos
Autoanticorpos/sangue , Citocinas/imunologia , Epidermólise Bolhosa/sangue , Epidermólise Bolhosa/imunologia , Pele/imunologia , Adolescente , Adulto , Epidermólise Bolhosa/genética , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Inherited epidermolysis bullosa (EB) is a group of skin diseases characterized by blistering of the skin and mucous membranes.There are four major types of EB (EB simplex, junctional EB, dystrophic EB and Kindler syndrome) caused by different gene mutations. Dystrophic EB is derived from mutations in the type VII collagen gene (COL7A1), encoding a protein which is the predominant component of the anchoring fibrils at the dermal-epidermal junction.For the first time in literature, we have evaluated the presence of anti-skin autoantibodies in a wider cohort of patients suffering from inherited EB and ascertained whether they may be a marker of disease activity. METHODS: Sera from patients with inherited EB, 17 with recessive dystrophic EB (RDEB), 10 with EB simplex (EBS) were analysed. As much as 20 patients with pemphigus vulgaris, 21 patients with bullous pemphigoid and 20 healthy subjects were used as controls.Anti-skin autoantibodies were tested in all samples with the Indirect Immunofluorescence (IIF) method and the currently available ELISA method in order to detect anti-type VII collagen, anti-BP180 and anti-BP230 autoantibodies. RESULTS: The mean concentrations of anti-type VII collagen autoantibodies titres, anti-BP180 and anti-BP230 autoantibodies were statistically higher in RDEB patients than in EBS patients.The sensitivity and specificity of the anti-type VII collagen ELISA test were 88.2% and 96.7%. The Birmingham Epidermolysis Bullosa Severity score, which is used to evaluate the severity of the disease, correlated with anti-skin autoantibodies titres. CONCLUSIONS: The precise pathogenic role of circulating anti-skin autoantibodies in RDEB is unclear. There is a higher prevalence of both anti-type VII collagen and other autoantibodies in patients with RDEB, but their presence can be interpreted as an epiphenomenon.