RESUMEN
Over the past several centuries, the integration of contemporary medical techniques and innovative technologies, like genetic sequencing, have played a pivotal role in enhancing our comprehension of congenital vascular and lymphatic disorders. Nonetheless, the uncommon and complex characteristics of these disorders, especially considering their formation during the intrauterine stage, present significant obstacles in diagnosis and treatment. Here, we review the intricacies of these congenital abnormalities, offering an in-depth examination of key diagnostic approaches, genetic factors, and therapeutic methods.
Asunto(s)
Enfermedades Linfáticas , Humanos , Enfermedades Linfáticas/terapia , Enfermedades Linfáticas/genética , Enfermedades Vasculares/congénito , Enfermedades Vasculares/genética , Enfermedades Vasculares/terapia , Enfermedades Vasculares/diagnóstico , Animales , Malformaciones Vasculares/genética , Malformaciones Vasculares/terapia , Vasos Linfáticos/anomalías , Predisposición Genética a la EnfermedadRESUMEN
The lymphatic system, crucial for tissue fluid balance and immune surveillance, can be severely impacted by disorders that hinder its activities. Lymphatic malformations (LMs) are caused by fluid accumulation in tissues owing to defects in lymphatic channel formation, the obstruction of lymphatic vessels or injury to lymphatic tissues. Somatic mutations, varying in symptoms based on lesions' location and size, provide insights into their molecular pathogenesis by identifying LMs' genetic causes. In this review, we collected the most recent findings about the role of genetic and inflammatory biomarkers in LMs that control the formation of these malformations. A thorough evaluation of the literature from 2000 to the present was conducted using the PubMed and Google Scholar databases. Although it is obvious that the vascular endothelial growth factor receptor 3 mutation accounts for a significant proportion of LM patients, several mutations in other genes thought to be linked to LM have also been discovered. Also, inflammatory mediators like interleukin-6, interleukin-8, tumor necrosis factor-alpha and mammalian target of rapamycin are the most commonly associated biomarkers with LM. Understanding the mutations and genes expression responsible for the abnormalities in lymphatic endothelial cells could lead to novel therapeutic strategies based on molecular pathways.
Asunto(s)
Anomalías Linfáticas , Vasos Linfáticos , Humanos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anomalías Linfáticas/genética , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/patología , Vasos Linfáticos/anomalías , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patología , Biomarcadores/metabolismoRESUMEN
We have studied the lymphatic phenotypes of 2 mutations, known to cause abnormalities of lymphatics in humans, in mice. The Cx47 R260C mutation (variably penetrant in humans heterozygous for it and causing limb lymphedema) had an adult mouse phenotype of hyperplasia and increased lymph nodes only in homozygous condition but we did not find any anatomical phenotype in day 16.5 homozygous embryos. Mice harboring the Sos1 mutation E846K (causing Noonan's in man which occasionally shows lymphatic dysplasia) had no adult heterozygous phenotype in lymphatic vessel appearance and drainage (homozygotes are early embryonic lethals) while day 16.5 heterozygous embryos also had no detectable anatomical phenotype.
Asunto(s)
Enfermedades Linfáticas , Vasos Linfáticos , Proteína SOS1 , Animales , Humanos , Ratones , Heterocigoto , Homocigoto , Vasos Linfáticos/anomalías , Vasos Linfáticos/embriología , Mutación , Fenotipo , Linfedema/embriología , Linfedema/genética , Enfermedades Linfáticas/embriología , Enfermedades Linfáticas/genética , Proteína SOS1/genética , Conexinas/genéticaRESUMEN
BACKGROUND: Schlemm's canal (SC) is a large vessel residing in the iridocorneal angle and is required to regulate aqueous humor outflow. Normal SC structure and function is indispensable for maintaining normal intraocular pressure, and elevated intraocular pressure is a risk factor for development of glaucoma. Recent reports have identified a key role of the angiopoietin-Tie2 pathway for SC development and function; however, the role of the orphan receptor Tie1 has not been clarified. METHODS: We used Tie1 knock out mice to study the function of Tie1 in SC development and function. Real-time quantitative polymerase chain reaction and Western blot analyses were used to verify Tie1 deletion. High-resolution microscopy of mouse SC whole mount and cross sections were used to study SC morphology. Measurement of intraocular pressure in live mice was used to study the impact of Tie1 on SC function. RESULTS: Tie1 is highly expressed in both human and mouse SC. Tie1 knock out mice display hypomorphic SC and elevated intraocular pressure as a result of attenuated SC development. CONCLUSIONS: Tie1 is indispensable for SC development and function, supporting it as a novel target for future SC-targeted glaucoma therapies and a candidate gene for glaucoma in humans.
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Cámara Anterior/enzimología , Cámara Anterior/crecimiento & desarrollo , Endotelio Corneal/enzimología , Receptor TIE-1/metabolismo , Animales , Humor Acuoso/fisiología , Glaucoma/etiología , Humanos , Presión Intraocular/fisiología , Vasos Linfáticos/anomalías , Vasos Linfáticos/enzimología , Vasos Linfáticos/fisiología , Ratones , Ratones Noqueados , Modelos Animales , Receptor TIE-1/deficiencia , Receptor TIE-1/genéticaRESUMEN
Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals, suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, which is indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting that the clearance of ß-amyloid and waste from the central nervous system may be impeded.
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Craneosinostosis/patología , Vasos Linfáticos/anomalías , Meninges/irrigación sanguínea , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Craneosinostosis/líquido cefalorraquídeo , Craneosinostosis/genética , Ratones , Ratones Endogámicos C57BL , Proteínas Represoras/genética , Proteína 1 Relacionada con Twist/genéticaRESUMEN
OBJECTIVE: Lymphatic malformations are characterized by the overgrowth of lymphatic vessels during development. Activation of PI3K/AKT and MAPK/ERK signaling pathways occur in isolated lymphatic malformation and in those associated with syndromes such as CLOVES and Klippel-Trenaunay. We aimed to assess the activation of these pathways in sporadic oral lymphatic malformations. STUDY DESIGN: A convenience sample of 14 formalin-fixed paraffin-embedded samples of oral lymphatic malformations underwent immunohistochemical reactions for the phosphorylated forms of AKT1 (pAKT-Ser473) and ERK1/2 (pERK1/2-Thr202/Tyr204), which are markers of PI3K/AKT and MAPK/ERK pathways activation, respectively. RESULTS: Positive staining for pAKT1 and pERK1/2 was observed in the endothelial cells in all samples of oral lymphatic malformations evaluated. CONCLUSIONS: Our results suggest that activation of PI3K/AKT and MAPK/ERK signaling pathways participates in the pathogenesis of oral lymphatic malformations.
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Vasos Linfáticos/anomalías , Sistema de Señalización de MAP Quinasas , Fosfatidilinositol 3-Quinasas , Células Endoteliales/metabolismo , Humanos , Boca , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
BACKGROUND: Mesenteric lymphatic malformations (LMs) represent rare congenital anomalies that can include chylous or nonchylous content. The pathologic mechanisms explaining this phenomenon are poorly understood and not yet described. Furthermore, the current management approach does not consider the contents of the mesenteric LMs. In the present study, we have defined the relationship between the lymphatic mesenteric cyst content and the histologic evidence of LMs within the bowel wall. METHODS: We retrospectively investigated all patients with mesenteric LMs treated surgically at our department from 1999 to 2018. RESULTS: A total of 11 patients (6 girls and 5 boys) were included in our analysis. Seven patients had presented with LMs located in the jejunal mesentery, three in the ileocecal region, and only one in the mesocolon transversum and omentum. Of the 11 children, 7 had had LMs with nonchylous content and 4 had presented with chylous content LMs. Intestinal resection was performed in all 4 patients with chylous content LMs and 4 patients with nonchylous content LMs. Histopathologic evaluation of the surgical specimens determined that only the LMs with chylous content displayed malformed lymphatic channels throughout the bowel wall. The resected small bowel of four patients with nonchylous content showed no LM extension throughout the intestinal wall. CONCLUSIONS: LMs with chylous content seem to develop from malformed lymphatic channels within the bowel wall. In such cases, segmental intestinal resection is mandatory. In contrast, mesenteric LMs with nonchylous content can potentially be treated without bowel resection if the blood supply can be preserved. This finding is, to the best of our knowledge, reported in the present study for the first time.
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Ascitis Quilosa/cirugía , Anomalías Linfáticas/cirugía , Vasos Linfáticos/cirugía , Quiste Mesentérico/cirugía , Adolescente , Niño , Preescolar , Ascitis Quilosa/diagnóstico por imagen , Femenino , Humanos , Recién Nacido , Anomalías Linfáticas/diagnóstico por imagen , Vasos Linfáticos/anomalías , Vasos Linfáticos/diagnóstico por imagen , Masculino , Quiste Mesentérico/diagnóstico por imagen , Mesenterio , Complicaciones Posoperatorias/etiología , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Dolor Abdominal/etiología , Vasos Linfáticos/anomalías , Enfermedades Pancreáticas/diagnóstico , Adulto , Femenino , Humanos , Vasos Linfáticos/diagnóstico por imagen , Vasos Linfáticos/patología , Enfermedades Pancreáticas/complicaciones , Enfermedades Pancreáticas/diagnóstico por imagen , Enfermedades Pancreáticas/patología , Tomografía Computarizada por Rayos XRESUMEN
Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.
Asunto(s)
Huesos/patología , Vasos Linfáticos , Osteólisis Esencial , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridonas/farmacología , Pirimidinonas/farmacología , Acrilonitrilo/análogos & derivados , Acrilonitrilo/farmacología , Compuestos de Anilina/farmacología , Animales , Modelos Animales de Enfermedad , Mutación con Ganancia de Función , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Linfangiogénesis/genética , Vasos Linfáticos/anomalías , Vasos Linfáticos/patología , Ratones , Osteólisis Esencial/genética , Osteólisis Esencial/patología , Transducción de Señal , Estructuras Linfoides Terciarias/genética , Estructuras Linfoides Terciarias/patologíaRESUMEN
Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.
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Vasos Sanguíneos/anomalías , Anomalías Linfáticas , Vasos Linfáticos/anomalías , Malformaciones Vasculares , Animales , Vasos Sanguíneos/metabolismo , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Anomalías Linfáticas/genética , Anomalías Linfáticas/metabolismo , Anomalías Linfáticas/patología , Anomalías Linfáticas/terapia , Vasos Linfáticos/metabolismo , Fenotipo , Factores de Riesgo , Malformaciones Vasculares/genética , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/patología , Malformaciones Vasculares/terapiaRESUMEN
Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell-autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.
Asunto(s)
Linfangiogénesis , Anomalías Linfáticas/genética , Anomalías Linfáticas/terapia , Vasos Linfáticos/anomalías , Mutación , Animales , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Anomalías Linfáticas/metabolismo , Anomalías Linfáticas/patología , Vasos Linfáticos/metabolismo , Fenotipo , Transducción de SeñalRESUMEN
BACKGROUND: To investigate whether the YAP/TAZ (Yes-associated protein/transcriptional coactivator with PDZ binding motif) pathway contributes to the pathogenesis of lymphatic malformations (LMs). METHODS: YAP, TAZ, CTGF (connective tissue growth factor), and Ki-67 were detected in LMs by immunohistochemistry. The colocalization of YAP and Ki-67 was analyzed by double immunofluorescence. Pearson's correlation and cluster analyses were performed to analyze the relationships between these proteins. Human dermal lymphatic endothelial cells (HDLECs) were used for mechanistic investigation. Rat models of LMs were established to investigate the role of the YAP pathway in LM development. RESULTS: Compared with those in normal skin, the expression levels of YAP, TAZ, CTGF, and Ki-67 were significantly upregulated in lymphatic endothelial cells (LECs) of LMs. Interestingly, YAP and CTGF presented much higher expression levels in infected LMs. In experiments in vitro, lipopolysaccharide (LPS) enhanced the expression of YAP in a concentration- and time-dependent manner via the increased phosphorylation of Erk1/2 (extracellular signal-regulated kinase 1/2). Moreover, the proliferation, invasion, and tubule formation of HDLECs increased significantly in accordance with the activation of the YAP signaling pathway. Furthermore, LM rat models validated that LPS facilitated the development of LMs, which was dependent on the activation of YAP. CONCLUSIONS: The data reveal that activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs. IMPACT: Compared with that in normal skin, the YAP signaling pathway was activated in LECs of LMs. Inhibiting the YAP signaling pathway attenuated the proliferation, invasion, and tubule formation of HDLECs. Additionally, the activation of the YAP signaling pathway could promote LM development in a rat model. Activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs. The YAP signaling pathway was activated in LMs. Inhibition of the YAP signaling pathway could promote regression of the lesions.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Endoteliales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfangiogénesis , Anomalías Linfáticas/metabolismo , Vasos Linfáticos/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Estudios de Casos y Controles , Movimiento Celular , Proliferación Celular , Células Cultivadas , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Antígeno Ki-67/metabolismo , Linfangiogénesis/efectos de los fármacos , Anomalías Linfáticas/genética , Anomalías Linfáticas/patología , Anomalías Linfáticas/prevención & control , Vasos Linfáticos/anomalías , Vasos Linfáticos/efectos de los fármacos , Ratas , Transducción de Señal , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Verteporfina/farmacología , Proteínas Señalizadoras YAPRESUMEN
Metabolism plays a pivotal role in the formation of the lymphatic vasculature. Pyruvate kinase M2 (PKM2) is typically a metabolic marker of proliferating cells and maintains the growth of vascular endothelial cells. In this study, the potential status of PKM2 in lymphatic endothelial cells and the pathogenesis of lymphatic malformations (LMs) was investigated. The glycolysis index, including glucose uptake, ATP, and lactate production, stayed at a relatively high level in human dermal lymphatic endothelial cells (HDLECs) compared with human umbilical vein endothelial cells, whereas the inhibition of PKM2 by shikonin or PKM2 knockdown significantly suppressed glycolysis, migration, tubular formation, and invasion of HDLECs. Moreover, compared with lymphatic vessels in healthy skin, lymphatic vessels of LMs expressed PKM2 highly, and this expression correlated with infection of LMs. Meanwhile, the overexpression of PKM2 in HDLECs strengthened the proliferation, migration, tubular formation, and invasion of HDLECs. The findings from further experiments in a rat LM model support that targeting PKM2 by shikonin significantly impedes the progression of LMs, even in an infected LM rat model. Taken together, these results indicate that PKM2 plays a pivotal role in the activation of LECs and promotes the progression of LMs, whereas the inhibition of PKM2 can effectively suppress the pathogenesis of LM lesions in the rat model.
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Células Endoteliales/enzimología , Anomalías Linfáticas/enzimología , Vasos Linfáticos/anomalías , Piruvato Quinasa/metabolismo , Animales , Femenino , Glucólisis/fisiología , Humanos , Vasos Linfáticos/enzimología , Ratas , Ratas WistarRESUMEN
Large abdominal lymphatic malformations (LMs) are rare and may occasionally cause life-threatening illness, especially when they involve the central lymphatic system, lumbar trunks, cisterna chyli, thoracic duct, and their major tributaries, forming complex lymphatic anomalies. These LMs are often accompanied by chylous leak in various locations, and treatment remains challenging. We report a case of large abdominal LM with chylous ascites, protein-losing enteropathy, vaginal chylous leak, and lower limb lymphedema successfully treated with microsurgical intra-abdominal lymphovenous anastomosis and discuss the technical details of the procedure.
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Ascitis Quilosa/cirugía , Anomalías Linfáticas/cirugía , Vasos Linfáticos/cirugía , Microcirugia , Abdomen , Anastomosis Quirúrgica , Niño , Ascitis Quilosa/diagnóstico por imagen , Ascitis Quilosa/etiología , Femenino , Humanos , Anomalías Linfáticas/complicaciones , Anomalías Linfáticas/diagnóstico por imagen , Vasos Linfáticos/anomalías , Vasos Linfáticos/diagnóstico por imagen , Linfedema/etiología , Enteropatías Perdedoras de Proteínas/etiología , Resultado del TratamientoAsunto(s)
Hernia Inguinal/complicaciones , Vasos Linfáticos/anomalías , Malformaciones Vasculares/diagnóstico , Venas/anomalías , Niño , Hernia Inguinal/diagnóstico , Hernia Inguinal/cirugía , Herniorrafia , Humanos , Imagen por Resonancia Magnética , Masculino , Ultrasonografía , Malformaciones Vasculares/complicacionesAsunto(s)
Enfermedades Linfáticas/complicaciones , Enfermedades Linfáticas/cirugía , Vasos Linfáticos/anomalías , Procedimientos de Cirugía Plástica/métodos , Extubación Traqueal/métodos , Cartílago/trasplante , Humanos , Laringoestenosis/patología , Laringoestenosis/cirugía , Enfermedades Linfáticas/diagnóstico , Vasos Linfáticos/patología , Masculino , Cuidados Posoperatorios , Estenosis Traqueal/patología , Estenosis Traqueal/cirugía , Resultado del TratamientoRESUMEN
Detailed imaging of the lymphatic system often requires direct injection of contrast into lymph nodes which can be technically challenging, time consuming, and produce painful stimuli. We sought to describe the use of non-contrast MR lymphography (NCMRL) for normal controls and patients with a variety of rare disorders associated with lymphatic pathologies. Two control subjects and five affected patients (decompensated Fontan circulation, central conducting lymphatic abnormality, familial lymphedema and two with Gorham-Stout disease) were studied. NCMRL images were segmented in a semiautomated fashion and the major lymphatic channels and thoracic duct (TD) highlighted for identification. Adequate imaging was available for both controls and 4/5 affected patients; the youngest patient could not be imaged given patient motion. For the two controls, the TD was seen in the expected anatomic location. For the decompensated Fontan patient, there were numerous tortuous lymphatic channels, predominantly in the upper chest and neck. For the familial lymphedema patient, a TD was not identified; instead, peripheral lymphatic collaterals near the lateral chest walls. For the first Gorham- Stout patient, the TD was enlarged with large intrathoracic lymph collections. For the second Gorham-Stout patient, there were bilateral TD with lymph collections in vertebral bodies. Using NCMRL, we were able to image normal and abnormal lymphatic systems. An important learning point is the potential need for sedation for younger patients due to long image acquisition times and fine resolution of the structures of interest.
Asunto(s)
Anomalías Linfáticas/diagnóstico por imagen , Linfografía/métodos , Imagen por Resonancia Magnética/métodos , Estudios de Casos y Controles , Humanos , Vasos Linfáticos/anomalías , Vasos Linfáticos/diagnóstico por imagen , Osteólisis Esencial/diagnóstico , Enfermedades Raras , Conducto Torácico/anomalíasRESUMEN
CASE PRESENTATION: A 35-year-old man was admitted for recurrent episodes of pneumonia. He complained of a 2-month history of exertional dyspnea and productive cough with whitish and viscous sputum which was poorly responsive to antibiotic therapy. He also reported a weight loss of 5 kg since the first symptoms appeared. There was no dysphagia, fever, or chest pain. He currently did not use medication and did not have a relevant medical history except a current 10 pack-year smoking history. He did not report any history of trauma or respiratory exposure to fats.
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Quilotórax , Dieta con Restricción de Grasas/métodos , Enfermedades Pulmonares/congénito , Pulmón , Linfangiectasia/congénito , Vasos Linfáticos , Neumonía , Adulto , Biopsia/métodos , Quilotórax/diagnóstico , Quilotórax/etiología , Diagnóstico Diferencial , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/dietoterapia , Enfermedades Pulmonares/fisiopatología , Linfangiectasia/diagnóstico , Linfangiectasia/dietoterapia , Linfangiectasia/fisiopatología , Vasos Linfáticos/anomalías , Vasos Linfáticos/diagnóstico por imagen , Linfografía/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Neumonía/diagnóstico , Neumonía/etiología , Recurrencia , Pruebas de Función Respiratoria/métodos , Esputo , Tomografía Computarizada por Rayos X/métodosAsunto(s)
Medios de Contraste/administración & dosificación , Embolización Terapéutica , Anomalías Linfáticas/diagnóstico por imagen , Anomalías Linfáticas/terapia , Vasos Linfáticos/diagnóstico por imagen , Ultrasonografía Intervencional , Adolescente , Femenino , Humanos , Vasos Linfáticos/anomalías , Punciones , Resultado del TratamientoRESUMEN
Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.