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1.
BMJ Case Rep ; 17(4)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575333

RESUMO

SummaryHereditary haemorrhagic telangiectasia (HHT) has an estimated prevalence of 1 in 5000-8000 individuals globally with pulmonary arteriovenous malformations (PAVMs) affecting approximately 15%-50% of HHT patients. Ischaemic stroke is a known complication of PAVMs that affects ≤30% of patients with PAVMs. Studies have shown that patients with PAVMs have ischaemic stroke a decade earlier than routine stroke. The predominant mechanism of ischaemic stroke in HHT patients is paradoxical embolism due to PAVMs, but most HHT-related PAVMs are asymptomatic. Additionally, HHT is often underdiagnosed in patients and poses a challenge to physicians due to its rarity. We present a case of a patient with ischaemic stroke who was subsequently diagnosed with HHT and found to have a PAVM on further evaluation. This case highlights the importance of using an individualised patient-centred stroke evaluation and screening for PAVMs in patients who had a stroke with possible or suspected HHT and definite HHT.


Assuntos
Fístula Arteriovenosa , Malformações Arteriovenosas , Isquemia Encefálica , AVC Isquêmico , Artéria Pulmonar/anormalidades , Veias Pulmonares/anormalidades , Acidente Vascular Cerebral , Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/terapia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/complicações , Isquemia Encefálica/complicações , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/diagnóstico , Artéria Pulmonar/diagnóstico por imagem , Hemorragia/complicações , AVC Isquêmico/complicações
2.
Eur Respir J ; 63(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38514094

RESUMO

BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, respectively, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored. METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients. RESULTS: 26 PAH patients were identified: 20 harbouring heterozygous GDF2 variants, one homozygous GDF2 variant, four heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female/male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3-40.6) WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders in BMP10 carriers. CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to the literature. BMP10 full phenotypic ramifications warrant further investigation.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Telangiectasia Hemorrágica Hereditária , Humanos , Masculino , Feminino , Adulto , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Hipertensão Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/complicações , Hipertensão Pulmonar Primária Familiar , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/genética , Fenótipo , Fator 2 de Diferenciação de Crescimento/genética , Estudos Multicêntricos como Assunto
3.
Genes (Basel) ; 15(3)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38540362

RESUMO

Hereditary hemorrhagic telangiectasia (HHT), also called Rendu-Osler syndrome, is a group of rare genetic diseases characterized by autosomal dominance, multisystemic vascular dysplasia, and age-related penetrance. This includes arteriovenous malformations (AVMs) in the skin, brain, lung, liver, and mucous membranes. The correlations between the phenotype and genotype for HHT are not clear. An HHT Chinese pedigree was recruited. Whole exome sequencing (WES) analysis, Sanger verification, and co-segregation were conducted. Western blotting was performed for monitoring ENG/VEGFα signaling. As a result, a nonsense, heterozygous variant for ENG/CD105: c.G1169A:p. Trp390Ter of the proband with hereditary hemorrhagic telangiectasia type 1 (HHT1) was identified, which co-segregated with the disease in the M666 pedigree. Western blotting found that, compared with the normal levels associated with non-carrier family members, the ENG protein levels in the proband showed approximately a one-half decrease (47.4% decrease), while levels of the VEGFα protein, in the proband, showed approximately a one-quarter decrease (25.6% decrease), implying that ENG haploinsufficiency, displayed in the carrier of this variant, may affect VEGFα expression downregulation. Pearson and Spearman correlation analyses further supported TGFß/ENG/VEGFα signaling, implying ENG regulation in the blood vessels. Thus, next-generation sequencing including WES should provide an accurate strategy for gene diagnosis, therapy, genetic counseling, and clinical management for rare genetic diseases including that in HHT1 patients.


Assuntos
Telangiectasia Hemorrágica Hereditária , Humanos , Endoglina/genética , Endoglina/metabolismo , Telangiectasia Hemorrágica Hereditária/genética , Genótipo , Heterozigoto , China
4.
Actas dermo-sifiliogr. (Ed. impr.) ; 115(3): 246-257, Mar. 2024. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-231397

RESUMO

Background: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. Objective: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. Methods A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. Results: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2–4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2–3; mean 2.61) vs 2 (IQR 2–3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. Conclusions DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments. (AU)


Antecedentes: La telangiectasia hemorrágica hereditaria (THH) se caracteriza por la presencia de telangiectasias y malformaciones arteriovenosas de mayor tamaño en diferentes órganos. Las telangiectasias a nivel mucocutáneo pueden sangrar y convertirse en un problema estético, afectando la calidad de vida (CdV). Sin embargo, aún no se ha definido su mejor enfoque terapéutico. Objetivo: Evaluar la eficacia y la seguridad del láser dual secuencial de longitud de onda de 595/1064nm (DWSL) en comparación con el láser de 1064nm (Nd:YAG) solo. Por otro lado, evaluar el deterioro de la calidad de vida en los pacientes con THH y su mejora tras la terapia con láser. Métodos: Estudio prospectivo, doble ciego, aleatorizado, comparativo, de cuerpo dividido (DWSL vs. Nd:YAG). Se registraron las características demográficas, clínicas y del tratamiento. La gravedad y el grado de mejora fueron evaluados por tres examinadores ciegos que calificaron las imágenes previas al tratamiento y posteriores al tratamiento en una escala de 5 puntos. Los pacientes cumplimentaron las pruebas Skindex-29 y FACE-Q® y se evaluó el dolor asociado al procedimiento y la satisfacción del paciente. Resultados: Se analizaron 111 áreas de tratamiento (55 tratadas con DWSL y 56 con Nd:YAG) de 26 pacientes. La mediana del número de sesiones de láser fue de 2 (rango intercuartílico [RIC] 2-4; media 2,90 vs. 2,88, respectivamente). La mediana de la puntuación de mejora, independientemente de la ubicación, fue significativamente mayor para Nd:YAG en comparación con DWSL: 3 (IQR 2-3; media 2,61) frente a 2 (IQR 2-3; media 2,32), p=0,031. Tanto el índice FACE-Q como los resultados de la prueba Skindex-29 mejoraron significativamente (p<0,001), y el 92,4% de los pacientes informaron un alto grado de satisfacción (≥8). No se informaron eventos adversos graves... (AU)


Assuntos
Humanos , Telangiectasia Hemorrágica Hereditária , Lasers de Estado Sólido , Qualidade de Vida , Malformações Arteriovenosas , Terapia a Laser , Telangiectasia Retiniana , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Actas dermo-sifiliogr. (Ed. impr.) ; 115(3): t246-t257, Mar. 2024. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-231398

RESUMO

Antecedentes: La telangiectasia hemorrágica hereditaria (THH) se caracteriza por la presencia de telangiectasias y malformaciones arteriovenosas de mayor tamaño en diferentes órganos. Las telangiectasias a nivel mucocutáneo pueden sangrar y convertirse en un problema estético, afectando la calidad de vida (CdV). Sin embargo, aún no se ha definido su mejor enfoque terapéutico. Objetivo: Evaluar la eficacia y la seguridad del láser dual secuencial de longitud de onda de 595/1064nm (DWSL) en comparación con el láser de 1064nm (Nd:YAG) solo. Por otro lado, evaluar el deterioro de la calidad de vida en los pacientes con THH y su mejora tras la terapia con láser. Métodos: Estudio prospectivo, doble ciego, aleatorizado, comparativo, de cuerpo dividido (DWSL vs. Nd:YAG). Se registraron las características demográficas, clínicas y del tratamiento. La gravedad y el grado de mejora fueron evaluados por tres examinadores ciegos que calificaron las imágenes previas al tratamiento y posteriores al tratamiento en una escala de 5 puntos. Los pacientes cumplimentaron las pruebas Skindex-29 y FACE-Q® y se evaluó el dolor asociado al procedimiento y la satisfacción del paciente. Resultados: Se analizaron 111 áreas de tratamiento (55 tratadas con DWSL y 56 con Nd:YAG) de 26 pacientes. La mediana del número de sesiones de láser fue de 2 (rango intercuartílico [RIC] 2-4; media 2,90 vs. 2,88, respectivamente). La mediana de la puntuación de mejora, independientemente de la ubicación, fue significativamente mayor para Nd:YAG en comparación con DWSL: 3 (IQR 2-3; media 2,61) frente a 2 (IQR 2-3; media 2,32), p=0,031. Tanto el índice FACE-Q como los resultados de la prueba Skindex-29 mejoraron significativamente (p<0,001), y el 92,4% de los pacientes informaron un alto grado de satisfacción (≥8). No se informaron eventos adversos graves... (AU)


Background: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. Objective: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. Methods: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. Results: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2–4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2–3; mean 2.61) vs 2 (IQR 2–3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. Conclusions: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments. (AU)


Assuntos
Humanos , Telangiectasia Hemorrágica Hereditária , Lasers de Estado Sólido , Qualidade de Vida , Malformações Arteriovenosas , Terapia a Laser , Telangiectasia Retiniana , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Eur J Med Genet ; 68: 104919, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38355093

RESUMO

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.


Assuntos
Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/patologia , Mutação , Endoglina/genética , Sequência de Bases , Cromossomos Humanos Par 9/genética , Receptores de Activinas Tipo II/genética
7.
Nihon Shokakibyo Gakkai Zasshi ; 121(2): 134-143, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38346761

RESUMO

A 34-year-old female patient with epigastric pain was admitted to our hospital. She reported an underlying condition of Rendu-Osler-Weber disease and a history of coil embolization for pulmonary arteriovenous fistula. A blood test revealed high hepatobiliary enzyme levels. An abdominal contrast-enhanced computed tomography revealed numerous arterioportal and arteriovenous shunts in the liver and a high-density area in the bile duct, which was diagnosed as biliary bleeding. She underwent transpapillary biliary drainage by endoscopic retrograde cholangiopancreatography, but recurrent biliary bleeding caused cholangitis, which was complicated by multiple liver abscesses. She was awaiting her turn for liver transplantation from brain-dead donors, but the liver abscesses were difficult to improve. Further, liver failure, septic pulmonary embolism, and disseminated intravascular coagulation were complicated. Thus, recurrent further biliary bleeding resulted in hemorrhagic shock, which required frequent blood transfusions. Furthermore, the continuous abscess to the intrahepatic bile duct in the anterior superior segment penetrated her diaphragm, causing hemothorax and eventually, death. Establishing progressive treatment, including liver transplantation, is considered necessary for this intractable disease.


Assuntos
Fístula Arteriovenosa , Abscesso Hepático , Falência Hepática , Telangiectasia Hemorrágica Hereditária , Humanos , Feminino , Adulto , Telangiectasia Hemorrágica Hereditária/complicações , Fístula Arteriovenosa/complicações , Falência Hepática/complicações , Colangiopancreatografia Retrógrada Endoscópica , Hemorragia
9.
J Clin Invest ; 134(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38357927

RESUMO

Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease is characterized by small arteriovenous malformations (AVMs) in mucocutaneous areas (telangiectases) and larger visceral AVMs in the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway. This Review presents up-to-date insights on this mutated signaling pathway and its crosstalk with proangiogenic pathways, in particular the VEGF pathway, that has allowed the repurposing of new drugs for HHT treatment. However, despite the substantial benefits of these new treatments in terms of alleviating symptom severity, this not-so-uncommon bleeding disorder still currently lacks any FDA- or European Medicines Agency-approved (EMA-approved) therapies.


Assuntos
Malformações Arteriovenosas , Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Telangiectasia Hemorrágica Hereditária/genética , Malformações Arteriovenosas/metabolismo , Transdução de Sinais/genética
10.
Cells ; 13(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38334677

RESUMO

Endothelial cells (ECs) respond to concurrent stimulation by biochemical factors and wall shear stress (SS) exerted by blood flow. Disruptions in flow-induced responses can result in remodeling issues and cardiovascular diseases, but the detailed mechanisms linking flow-mechanical cues and biochemical signaling remain unclear. Activin receptor-like kinase 1 (ALK1) integrates SS and ALK1-ligand cues in ECs; ALK1 mutations cause hereditary hemorrhagic telangiectasia (HHT), marked by arteriovenous malformation (AVM) development. However, the mechanistic underpinnings of ALK1 signaling modulation by fluid flow and the link to AVMs remain uncertain. We recorded EC responses under varying SS magnitudes and ALK1 ligand concentrations by assaying pSMAD1/5/9 nuclear localization using a custom multi-SS microfluidic device and a custom image analysis pipeline. We extended the previously reported synergy between SS and BMP9 to include BMP10 and BMP9/10. Moreover, we demonstrated that this synergy is effective even at extremely low SS magnitudes (0.4 dyn/cm2) and ALK1 ligand range (femtogram/mL). The synergistic response to ALK1 ligands and SS requires the kinase activity of ALK1. Moreover, ALK1's basal activity and response to minimal ligand levels depend on endocytosis, distinct from cell-cell junctions, cytoskeleton-mediated mechanosensing, or cholesterol-enriched microdomains. However, an in-depth analysis of ALK1 receptor trafficking's molecular mechanisms requires further investigation.


Assuntos
Malformações Arteriovenosas , Telangiectasia Hemorrágica Hereditária , Humanos , Células Endoteliais , Ligantes , Telangiectasia Hemorrágica Hereditária/genética , Transdução de Sinais , Proteínas Morfogenéticas Ósseas
11.
Cardiovasc Intervent Radiol ; 47(3): 360-365, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38180506

RESUMO

PURPOSE: To evaluate the safety, technical success and short-term effectiveness of polyurethane-covered stent (PK Papyrus, BioTronik, Berlin) in the treatment of pulmonary arteriovenous malformations (PAVMs) that are not amenable to embolotherapy. MATERIALS AND METHODS: In this IRB-approved, retrospective study, data from patients who received polyurethane-covered stents for exclusion of PAVMs were analyzed. The study included 5 patients (all women) with a median age of 40 years (range 25-60). Patients presented with hypoxemia, TIAs, and/or epistaxis; 4 were confirmed to have HHT. All had multiple PAVMs diagnosed on chest CT and underwent embolization with other devices in addition to the polyurethane-covered stent. The indication for stent placement in all cases was a short and/or tortuous feeding artery. Safety was assessed by immediate or short-term complications, e.g., migration, stent thrombosis, and fracture. Technical success was defined as the ability to accurately place the stent at the intended location. Effectiveness was defined as successful exclusion of PAVM with no perfusion across the AVM. RESULTS: Technical success of stent placement was 100%. AVM exclusion rate was 80% after single stent deployment; in the case of incomplete exclusion, success was achieved using an overlapping stent to completely cover a second feeding artery. During the median follow-up period of 5 months (range 2-10), all stents remained patent, and AVMs were excluded without other complications. CONCLUSION: Exclusion of PAVMs with polyurethane-covered stents is technically feasible, safe, and shows short-term effectiveness for PAVMs with a short/tortuous feeding artery when traditional embolization techniques are not possible.


Assuntos
Fístula Arteriovenosa , Malformações Arteriovenosas , Embolização Terapêutica , Artéria Pulmonar/anormalidades , Veias Pulmonares , Veias Pulmonares/anormalidades , Telangiectasia Hemorrágica Hereditária , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Poliuretanos , Telangiectasia Hemorrágica Hereditária/terapia , Estudos Retrospectivos , Resultado do Tratamento , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/terapia , Malformações Arteriovenosas/complicações , Veias Pulmonares/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Stents/efeitos adversos , Embolização Terapêutica/métodos
12.
Actas Dermosifiliogr ; 115(3): T246-T257, 2024 Mar.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38185205

RESUMO

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. OBJECTIVE: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. METHODS: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. RESULTS: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2-4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2-3; mean 2.61) vs 2 (IQR 2-3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. CONCLUSIONS: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments.


Assuntos
Alumínio , Lasers de Corante , Lasers de Estado Sólido , Telangiectasia Hemorrágica Hereditária , Telangiectasia , Ítrio , Humanos , Lasers de Corante/efeitos adversos , Lasers de Estado Sólido/efeitos adversos , Neodímio , Estudos Prospectivos , Qualidade de Vida , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia/etiologia , Telangiectasia/radioterapia , Resultado do Tratamento
13.
Clin Genet ; 105(5): 543-548, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38225712

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.


Assuntos
Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/genética , Endoglina/genética , Japão/epidemiologia , Mutação , Testes Genéticos , Receptores de Activinas Tipo II/genética
14.
Acta Neurochir (Wien) ; 166(1): 21, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38231447

RESUMO

OBJECTIVE: Brain arteriovenous malformations (AVMs) in patients with hereditary hemorrhagic telangiectasia (HHT) present different characteristics from sporadic AVMs, and they have lower initial bleeding rates. Conservative management is usually preferred for the treatment of these lesions. In this case study, we present the largest series of HHT patients treated with stereotactic radiosurgery to date. METHODS: We identified eight patients with HHT and 14 AVMs. We retrospectively collected clinical, radiographic, and treatment characteristics of the patients and each AVM. RESULTS: Most patients in our sample presented with small AVMs. The median volume of these AVMs was 0.22 cm3 (IQR 0.08-0.59). Three out of eight patients presented with initial intracerebral hemorrhage (ICH). The majority of lesions had low (12/14) Spetzler-Martin grades (I-II). Median maximum and margin doses used for treatment were 36.2 (IQR 35.25-44.4) and 20 (IQR 18-22.5) Gy, respectively. The overall obliteration rate after SRS was 11/14, and the median time to obliteration across all 11 obliterated AVMs was 35.83 months (IQR, 17-39.99). Neurological status was favorable with all patients having a mRS of 0 or 1 at the last follow-up. Symptomatic radiation-induced changes (RIC) after SRS were low (7.1%), and there were no permanent RIC. CONCLUSIONS: Patients with HHT who present with multiple brain AVMs are generally well served by SRS. Obliteration can be achieved in the majority of HHT patients and with a low complication rate. In the current study, initial hemorrhage rates prior to SRS were noticeable which supports the decision to treat these AVMs. Future studies are needed to better address the role of SRS for HHT patients harboring ruptured and unruptured AVMs.


Assuntos
Malformações Arteriovenosas , Radiocirurgia , Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/cirurgia , Estudos Retrospectivos , Encéfalo
15.
Traffic ; 25(1): e12928, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38272447

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000-8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFß homodimeric co-receptor. It was previously shown that some endoglin HHT1-causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER-associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER-retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA-tagged ER-retained mutants formed heterodimers with Myc-tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER-retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.


Assuntos
Telangiectasia Hemorrágica Hereditária , Humanos , Alelos , Endoglina/genética , Retículo Endoplasmático/metabolismo , Mutação , Receptores de Superfície Celular/genética , Receptores de Fatores de Crescimento , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/metabolismo
16.
Eur J Neurol ; 31(2): e16128, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37955551

RESUMO

BACKGROUND AND PURPOSE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disease with fragile blood vessels and vascular malformations, potentially causing neurological manifestations, including stroke and cerebral abscesses. The study aimed to investigate neurological manifestations in the Danish HHT database, focusing on pulmonary arteriovenous malformations (PAVMs) as a risk factor for cerebral events. METHODS: Retrospective analysis of the Danish HHT database was conducted, cross-referencing neurological outcomes with the Danish Apoplexy Register for accuracy. Patients were stratified by HHT type. Primary outcomes included ischaemic stroke, transient ischaemic attack and cerebral haemorrhage. Secondary outcomes comprised age, age at HHT diagnosis, age at cerebral ischaemic event, and PAVM and cerebral arteriovenous malformation status. RESULTS: Six hundred and sixty-four HHT patients were included. PAVM was diagnosed in 54% of patients, with higher prevalence in HHT type 1 (70%) compared to HHT type 2 (34%) and juvenile polyposis HHT (66%). Ischaemic stroke or transient ischaemic attack occurred in 12.5%, with a higher risk associated with macroscopic PAVM. Logistic regression showed a nearly 10 times increased risk of ischaemic stroke with macroscopic PAVM. Cerebral abscesses occurred in 3.2% of patients, all with macroscopic PAVM. Incomplete PAVM closure increased cerebral abscess risk. CONCLUSION: This study provides valuable insights into the prevalence of neurological manifestations and vascular events in HHT patients. The presence of PAVM was associated with an increased risk of ischaemic stroke, highlighting the importance of early screening and intervention. The findings emphasize the need for comprehensive management strategies targeting both vascular and neurological complications in HHT patients, especially regarding secondary stroke prevention.


Assuntos
Abscesso Encefálico , Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/epidemiologia , Telangiectasia Hemorrágica Hereditária/diagnóstico , Estudos Retrospectivos , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/epidemiologia , Isquemia Encefálica/complicações , Isquemia Encefálica/epidemiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , AVC Isquêmico/complicações , Abscesso Encefálico/complicações , Abscesso Encefálico/epidemiologia
18.
Inn Med (Heidelb) ; 65(1): 71-75, 2024 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-37418022

RESUMO

A 43-year-old female patient with a brain abscess and a complicated clinical course was diagnosed with hereditary haemorrhagic telangiectasia (HHT) at the Martin Zeitz Centre for Rare Diseases in Hamburg, Germany. The brain abscess was caused by pulmonary arteriovenous malformations (AVM), a typical finding in HHT. Patients with cryptogenic brain abscess should be screened for pulmonary AVM and HHT. This case report illustrates the importance of patient history and interdisciplinary exchange in patients with a broad clinical spectrum as well as interdisciplinary treatment in the case of complications of rare diseases.


Assuntos
Malformações Arteriovenosas , Abscesso Encefálico , Telangiectasia Hemorrágica Hereditária , Feminino , Humanos , Adulto , Telangiectasia Hemorrágica Hereditária/complicações , Doenças Raras/complicações , Malformações Arteriovenosas/complicações , Pulmão , Abscesso Encefálico/diagnóstico por imagem
19.
Ann Otol Rhinol Laryngol ; 133(1): 58-62, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37377016

RESUMO

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease and epistaxis is the most common symptom. This can be treated conservatively but severe cases may require operative interventions. Endoscopic endonasal coblation of HHT lesions has been used successfully but postoperative pain management has not been well described. OBJECTIVES: This study aimed to assess levels of postoperative pain and opioid use among patients with HHT who underwent coblation of sinonasal lesions. METHODS: This is a longitudinal, prospective cohort study of adult patients undergoing endoscopic endonasal coblation for treatment of HHT lesions with or without bevacizumab injection between November 2019 and March 2020 at a single academic university hospital. Patients were given preoperative questionnaires and contacted via telephone 48 hours after surgery. If they reported using opioids for pain control, they were called every 2 days until they no longer used these medications. RESULTS: Fourteen cases, including 13 unique patients, were included in this study. Opioids were ordered on discharge in 4 cases and the average morphine milligram equivalent prescribed on discharge was 41. The median pain score on postoperative day (POD) 2 was 4 of 10. Twelve patients reported using acetaminophen and 4 were using opioid pain medications. Of those using opioid pain medications, only 1 patient was using opioid pain medication by POD 4 and denied any use after POD 10. CONCLUSION: This study is the first to analyze postoperative pain management and opioid prescribing patterns in HHT patients undergoing endonasal coblation of telangiectasias. Postoperative pain was mild to moderate and most patients stopped using opioid medications by POD 4, although the majority of patients solely used acetaminophen. Future studies with increased sample size will be useful to further identify predictors of need for analgesics postoperatively and other non-opioid adjuncts for pain control.


Assuntos
Analgésicos Opioides , Telangiectasia Hemorrágica Hereditária , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/cirurgia , Acetaminofen/uso terapêutico , Estudos Prospectivos , Padrões de Prática Médica , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia
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