Molecular and Cellular Characterization of Primary Endothelial Cells from a Familial Cavernomatosis Patient.

Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene (CCM1/Krit1, CCM2, CCM3) and its origin (spontaneous or familial), different types of this disease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression profiles of these cells were analyzed and compared to primary ECs from a healthy donor. The mutation of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased expression of genes involved in intercellular junction formation, angiogenesis, and vascular homeostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and somewhat predisposed to vascular damage.

Brain and/or Spinal Cord Tumors Accompanied with Other Diseases or Syndromes.

Several medical conditions that interest both the brain and the spinal cord have been described throughout the history of medicine. Formerly grouped under the term Phacomatosis because lesions of the eye were frequently encountered or genodermatosis when typical skin lesions were present, these terms have been progressively discarded. Although originally reported centuries ago, they still represent a challenge for their complexity of cure. Nowadays, with the introduction of advanced genetics and the consequent opportunity of whole-genome sequencing, new single cancer susceptibility genes have been identified or better characterized; although there is evidence that the predisposition to a few specific tumor syndromes should be accounted to a group of mutations in different genes while certain syndromes appeared to be manifestations of different mutations in the same gene adding supplementary problems in their characterization and establishing the diagnosis. Noteworthy, many syndromes have been genetically determined and well-characterized, accordingly in the near future, we expect that new targeted therapies will be available for the definitive cure of these syndromes and other gliomas (Pour-Rashidi et al. in World Neurosurgery, 2021). The most common CNS syndromes that will be discussed in this chapter include neurofibromatosis (NF) types 1 and 2, von Hippel-Lindau (VHL) disease, and tuberous sclerosis complex (TSC), as well as syndromes having mostly extra-neural manifestations such as Cowden, Li-Fraumeni, Turcot, and Gorlin syndromes.

"Radiologically Isolated" Spinal Cavernoma Associated with Familial Cerebral Cavernomatosis.

We describe a 45 year-old woman with a randomly discovered cavernous malformation of the cervical cord following investigation for neck injury. She had multiple brain cavernomas increasing in number over the following two years. She was finally diagnosed with familial cavernomatosis due to a PDCD10 mutation (CCM3).

Molecular diagnosis in cerebral cavernous malformations. / Diagnóstico molecular de cavernomatosis cerebral.

INTRODUCTION: Cerebral cavernous malformations (CCMs; OMIM 116860) are enlarged vascular cavities without intervening brain parenchyma whose estimated prevalence in the general population is between 0.1% and 0.5%. Familial CCM is an autosomal dominant disease with incomplete clinical and radiological penetrance. Three genes have been linked to development of the lesions: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. DEVELOPMENT: The aetiological mutation is not detected in a large percentage of cases and new approaches are therefore needed. The aim of this review is to analyse current molecular techniques and the possible mutations or variations which can be detected in a molecular genetics or molecular biology laboratory. Likewise, we will analyse other alternatives that may help detect mutations in those patients showing negative results. CONCLUSIONS: A molecular diagnosis of cerebral cavernous malformations should provide at least the copy number variation and sequencing of CCM genes. In addition, appropriate genetic counselling is a crucial source of information and support for patients and their relatives.

[Results of the mesoportal bypass (Rex shunt) in the treatment of idiopathic extrahepatic portal vein obstruction in children]. / Resultados del shunt mesoportal de Rex en el tratamiento de la trombosis portal extrahepática idiopática.

BACKGROUND: Extrahepatic portal vein obstruction (EPVO) is the principal cause of portal hypertension in children. The objective of this study was to analyze the capacity of the surgical technique that creates a mesoportal shunt to treat changes caused by EPVO. METHODS: Retrospective review of patients with idiopathic EPVO who underwent a mesoportal shunt and analysis of the changes in the number of leucocytes, platelets, prothrombin time and spleen size one year after the surgery. RESULTS: Twelve patients underwent surgery, out of which 10 had prior leukopenia, 11 thrombopenia, 9 longer prothrombin times and all had hypersplenism. One patient suffered a postoperative shunt thrombosis, was reoperated and underwent a change in the operative technique. The remaining patients (92%) have functioning shunts 4.3 ± 2.5 years after surgery, and none have suffered any episode of gastrointestinal bleeding. One year after surgery, there were significant changes in the number of platelets, prothrombin time and spleen size, with no significant changes in the number of leukocytes. However, the number of patients who went from a leukopenic to a normal state was significant, as happened with changes in prothrombin time. CONCLUSIONS: Mesoportal Rex shunt improves some of the disorders caused by portal hypertension in children suffering EPVO, with a high rate of surgical success. This technique should be of first choice in these patients.

OBJETIVOS: La trombosis portal extrahepática (TPEH) es la causa más frecuente de hipertensión portal en el niño. El objetivo de este estudio es analizar la utilidad de la técnica quirúrgica que crea un shunt mesoportal para mejorar o revertir las alteraciones causadas por la TPEH. MATERIAL Y METODOS: Revisión retrospectiva de los pacientes con TPEH idiopática sometidos al shunt mesoportal y análisis de los cambios en la cifra de leucocitos, plaquetas, tiempo de protrombina y tamaño del bazo al año de la cirugía. RESULTADOS: De los 12 pacientes intervenidos, 10 tenían leucopenia, 11 plaquetopenia, 9 un tiempo de protrombina alargado y todos presentaban hiperesplenismo. Una paciente sufrió una trombosis postoperatoria del shunt por la que fue reoperada con cambio de la técnica quirúrgica. El resto de pacientes (92%) tienen un shunt funcionante con un seguimiento 4,3 ± 2,5 años y no han sufrido ningún sangrado gastrointestinal. Al año de la cirugía, observamos cambios significativos en el número total de plaquetas, tiempo de protrombina y tamaño del bazo, no siendo estos cambios significativos para la cifra de leucocitos. Sin embargo, el número de pacientes que pasó de estar leucopénico a tener cifras normales de leucocitos, sí fue significativo, hecho que también ocurrió en el caso de las alteraciones en el tiempo de protrombina. CONCLUSIONES: El shunt mesoportal de Rex mejora de manera efectiva las alteraciones asociadas a la hipertensión portal por TPEH, con una alta tasa de éxito, por lo que debería ser la técnica de elección en estos pacientes.

Unexpected disappearance of portal cavernoma on long-term anticoagulation.

Idiopathic non-cirrhotic portal hypertension is a rare disease of unknown etiology. Patients with idiopathic non-cirrhotic portal hypertension have an increased risk of developing portal vein thrombosis and this is especially prevalent when HIV is also present. We describe a unique case of a patient with idiopathic non-cirrhotic portal hypertension associated to HIV, who developed acute portal vein thrombosis that despite anticoagulation transformed in portal cavernoma and disappeared completely after five years of follow-up on continuous anticoagulation.

The dilemma of choosing obstetrics and anesthesia techniques in a patient with cerebral cavernomatosis: a case report.

This report describes the case of a pregnant woman who arrived for preanesthetic assessment of External Cephalic Version (ECV) for fetus in breech presentation and cesarean section in case of ECV failure. Although the technique seems simple, attempts to rotate the fetus can result in elevated intracranial pressure, which might cause malformation bleeding. The most appropriate anesthetic technique in cases of arteriovenous malformations during C-sections has not been determined. Neuroaxial anesthesia is safe only in stable brain cavernomas, but the presence of spinal malformations contraindicates it. Anesthetic goals include stabilizing the blood pressure and reducing the risk of rupture.

Magnetic Resonance Imaging of Multiple Cerebral and Spinal Cavernous Malformations of a Patient with Dementia and Tetraparesis.

Cavernomas are rare cerebrovascular malformations that usually occur in sporadic forms with solitary lesions located most often in the hemispheric white matter, but also in the infratentorial or spinal region. Multiple lesions at different CNS levels are considered a hallmark for the familial form of the disease. The diagnostic modality of choice for cerebral cavernous malformations (CCMs) is magnetic resonance imaging (MRI). We present an intriguing case of a 65-year-old male admitted to our hospital with tetraparesis and cognitive impairment where highly sensitive MRI sequences identified many cerebral cavernous lesions at the supra-, infratentorial and cervical-thoracic spine levels, some of them with recent signs of bleeding in a patient with oral anticoagulant therapy due to atrial fibrillation. The mechanism of cognitive impairment in this patient is most probably the interruption of strategic white matter tracts, as it is known to happen in other subcortical vascular pathologies. MRI can be helpful not only in mapping the anatomical distribution of lesions, but also in weighing the risks and making decisions regarding whether or not to continue oral anticoagulant therapy.

Cholestatic Jaundice Secondary to Portal Hypertensive Biliopathy Regarding a Case of Cavernous Transformation of the Portal Vein

Portal hypertensive biliopathy comprises the anatomical and functional abnormalities of the intra- and extrahepatic biliary tract, cystic duct, and gallbladder in patients with portal hypertension. The compromise of the bile duct usually occurs in portal obstruction due to the cavernous transformation of the portal vein (CTPV). We present a case of a young patient with a recent history of portal hypertension and CTPV who presented with an episode of cholestatic hepatitis. Studies documented an image of nodular appearance with extrinsic compression of the distal bile duct compatible with a tumor-like cavernoma. Effective endoscopic treatment was performed using endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and biliary stenting.

La biliopatía hipertensiva portal comprende las anomalías anatómicas y funcionales del tracto biliar intra- y extrahepático, el conducto cístico y la vesícula biliar en pacientes con hipertensión portal. El compromiso de la vía biliar suele presentarse en obstrucción portal debido a transformación cavernomatosa de la porta. Presentamos un caso de un paciente joven, con historia reciente de hipertensión portal y cavernomatosis de la porta, que presentó un episodio de hepatitis colestásica y en estudios se le documentó una imagen de apariencia nodular con compresión extrínseca de la vía biliar distal compatible con tumor-like cavernoma. En este caso se realizó un tratamiento endoscópico efectivo mediante colangiopancreatografía retrógrada endoscópica (CPRE), esfinterotomía y stent biliar.

Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: a susceptibility-weighted imaging study with 7-Tesla MRI.

OBJECTIVE Multiple cerebral cavernous malformations (CCMs) are rare lesions that occur in sporadic or familial form. Depending on the disease form, the natural history and treatment of the lesions strongly vary. Molecular analysis of an underlying germline mutation (CCM1-3) is the most sensitive screening method to distinguish between sporadic and familial cases. However, based on the different pathomechanisms that are believed to be involved in either form, significant distinctions in the CCM-associated cerebral venous angioarchitecture should be detectable. This has not been systematically studied. METHODS A consecutive series of 28 patients with multiple CCMs (681 total) diagnosed on 1.5-T MRI underwent genetic screening for CCM1-3 mutations and high-resolution susceptibility-weighted imaging (SWI) of the cerebral venous angioarchitecture with 7-T MRI. Imaging data were analyzed to examine the CCM-associated venous angioarchitecture. Results were correlated with findings of molecular analysis for CCM1-3 mutations. RESULTS Two different SWI patterns (sporadic and familial) were found. The presence of associated developmental venous anomalies correlated with negative screening for germline mutations (11 sporadic) in all cases. All patients with confirmed familial disease showed normal underlying venous angioarchitecture. Additionally, a very unusual case of a probable somatic mutation is presented. CONCLUSIONS The SWI results of the venous angioarchitecture of multiple CCMs correlate with sporadic or familial disease. These results are consistent with the theory that venous anomalies are causative for the sporadic form of multiple CCMs.

Cavernomatosis de la porta: presentación de un caso / Portal cavernomatosis: a case report

Fundamento: La cavernomatosis portal es una enfermedad poco frecuente causada por la trombosis de la vena porta, que provoca hipertensión portal (HP). Se ha relacionado con la realización de cateterismo umbilical, traumatismos abdominales e infecciones del período neonatal. La presentación clínica más frecuente es la hemorragia digestiva alta, con o sin melena, esplenomegalia, red venosa colateral y en etapas tardías puede observarse pancitopenia. Los métodos diagnósticos son ecografía abdominal, endoscopía digestiva y la angiotomografía. El diagnóstico definitivo es anatomopatológico. La literatura internacional y nacional es escasa para esta enfermedad, predominando el reporte de casos referidos a la edad pediátrica. Objetivo: presentar las características que definen esta enfermedad, en ocasión de darle seguimiento terapéutico a un paciente. Presentación de caso: se presenta un paciente de 20 años de edad, cuyo diagnóstico fue eventual por hallazgo ultrasonográfico en el periodo neonatal, con retraso madurativo y malnutrición proteico-energética. Conclusiones: la cavernomatosis portal o transformación cavernomatosa de la porta se define como la dilatación de las venas paracoledocianas y epicoledocianas generalmente secundaria a una trombosis portal, con una escasa prevalencia, fundamentalmente en edades pediátricas, que constituye la primera causa de hipertensión portal en este grupo etario. Provoca retardo del desarrollo pondoestatural, malnutrición proteicoenergética y sangramientos digestivos.

Background: Portal cavernomatosis is a rare disease caused by portal vein thrombosis, causing portal hypertension. It has been associated with performing umbilical catheterization, abdominal trauma and infections in the neonatal period. The most frequent clinical presentation is bleeding upper digestive, with or without melena, splenomegaly, collateral venous network and pancytopenia can be observed in late stages. Diagnostic methods are abdominal ultrasound, digestive endoscopy, and angiotomography. The definitive diagnosis is pathological. The international and national literature is scarce for this disease, with the predominant reporting of cases referring to pediatric age. Objective: to present the characteristics that define this disease, on the occasion of giving therapeutic follow-up to a patient. Case presentation: a 20-year-old patient is presented, whose diagnosis was eventual by ultrasound finding in the neonatal period, with maturational delay and protein-energy malnutrition. Conclusions: portal cavernomatosis or cavernomatous transformation of the Porta is defined as the dilation of the paracholedocian and epicoledocian veins generally secondary to portal thrombosis, with a low prevalence, mainly at pediatric ages, which is the leading cause of portal hypertension in this group. etareo. It causes delayed development of the body, protein-energy malnutrition and digestive bleeding.

Cavernomatosis múltiple y aneurisma cerebral trombosado: una asociación inusual / Cavernous haemangioma multiple and brain aneurysm thrombosed: an unusual association

Los cavernomas son malformaciones angiográficamente ocultas, pueden ser únicos o múltiples y esporádica o familiar.Suelen asociarse a otras malformaciones vasculares como las anomalías de drenaje venoso, sin embargo no es habitual su asociación con aneurismas cerebrales. Los aneurismas son malformaciones evidenciables en angiografía, sin embargo cuando se encuentran trombosados puede dificultarse su diagnostico, observándose en algunos casos como lesiones pseudotumorales. Nuestro objetivo es exponer una rara asociación entre cavernomatosis múltiple y aneurisma cerebral trombosado en un paciente pediátrico. Presentamos una paciente de 2 años de edad con diagnóstico de cavernomatosis múltiple y aneurisma cerebral trombosado. Se realiza una revisión de la literatura de ambas entidades y su rara asociación, medianteuna búsqueda exhaustiva en la base de datos de PUBMED Y COCHRANE utilizando las siguientes palabras claves: Cavernous angioma. Familial cavernomatosis. Hemorrhagic stroke. Multiple cavernomatosis. Cerebral aneurysm. Thrombosed aneurysm. Se discute la epidemiologia, diagnóstico y manejo quirúrgico de la cavernomatosis múltiple y sus asociaciones, preconizando fundamentalmente la evaluación pre quirúrgica de estos pacientes. No encontramos ningún caso de asociación entre cavernomatosis múltiple y aneurismas en nuestra revisión bibliográfica. Dado que se pueden presentar como lesiones pseudotumorales, la tomografía computada, resonancia magnética y la angiografía cerebral son métodos fundamentales para llegar a un diagnostico prequirúrgico certero. La indicación quirúrgica debe ser evaluada individualmente en cada paciente, y se debe realizar un seguimiento clínico-imagenologico.

Cavernomas are angiographically occult malformations may be single or multiple and sporadic or familial. Usually associated with other vascular malformations such as venous drainage anomalies, however it is not common its association with brain aneurysms. Aneurysms are into evidence malformations in angiography, however when they meet their diagnosis can be difficult thrombosed observed in some cases as pseudotumoral injuries. Our goal is to present a rare association between multiple cavernous haemangioma and thrombosed cerebral aneurysm in a pediatric patient. We present a patient 2 years old diagnosed with multiple cavernous haemangioma and thrombosed cerebral aneurysm. A review of the literature of both entities and its rare association is done through an exhaustive search in the database PUBMED and COCHRANE using the following keywords: Cavernous angioma. Familial cavernous haemangioma. Hemorrhagic stroke. Multiple cavernous haemangioma. Brain aneurysm. Thrombosed aneurysm. The epidemiology, diagnosis and surgical management of multiple cavernous haemangioma and their associations is discussedessentially advocating the presurgical evaluation of these patients. No case of association between multiple cavernous haemangioma and aneurysms in our literature review. Because can be presented as pseudotumoral lesions, computed tomography, magnetic resonance imaging and cerebral angiography are fundamental methods to reach an certain diagnosis preoperatively. The surgical indication should be evaluated individually for each patient, and should be performed a clinical-imaging follow-up.

Cavernomatosis cerebral múltiple: primer reporte de caso en Perú / Multiple cerebral cavernous: first case report in Peru

La cavernomatosis cerebral (CC), única o múltiple, es la presencia de conductos vasculares distendidos, angiográficamente ocultos, por lo cual clásicamente eran hallazgos incidentales intraoperatorios o en autopsias. Actualmente la resonancia magnética (RM) cerebral, permite identificar éstas lesiones en un mayor número de pacientes. Las manifestaciones clínicas son hemorragias intracerebrales, crisis epilépticas y cefalea. Se reporta el caso de un varón de 55 años, sin antecedentes de importancia que ingresó por presentar cefalea y crisis de arresto del habla. El examen físico fue normal. Estudios tomográficos previos mostraron una lesión hemorrágica única, al realizarse una RM cerebral con protocolo T2-eco gradiente se evidencia múltiples imágenes compatibles con CC múltiple. Es el primer reporte de CC múltiple, entidad poco diagnosticada, que se debe sospechar en pacientes sin antecedentes de riesgo vascular que debutan con hemorragias intracerebrales, crisis epilépticas y/o cefaleas; constituyendo la RM cerebral en protocolo T2-eco gradiente, el estudio indicado para el diagnóstico.

Cerebral cavernomatosis (CC), single or multiple, is the presence of distended vascular channels, angiographically occult, for that, they are classically incidental intraoperative findings at autopsy. Currently the magnetic resonance imaging (MRI) let us identify these lesions in a larger number of patients. Clinical manifestations are intracerebral hemorrhages, seizures and headache. A male, 55, no history of significance is reported; he was admitted for headache and some months later presents speech arrest crisis. On physical examination, nothing unusual. Previous tomographic studies showed a hemorrhagic lesion, when the brain MRI with T2-eco gradient protocol was performed, multiple images observed, were compatible with multiple CC. This is the first report of multiple CC, unfrequent entity that should be suspected in patients with no history of vascular risk who present intracerebral hemorrhage, seizure and / or headache; being the brain MRI, the study indicated for diagnosis.

Presentación de un caso de cavernomatosis de la porta en Pediatría / A case presentation of Porta´s cavernomatosis in Pediatrics

Transicional masculino, blanco, con antecedentes de distress respiratorio severo al nacer que necesitó de cateterización venosa umbilical y ventilación mecánica prolongada en la etapa neonatal precoz, con retardo del desarrollo psicomotor que ingresa en esta ocasión por vómitos y deposiciones de mala calidad que se interpreta como una enfermedad diarreica aguda (EDA) de etiología viral y que en el transcurso de la misma hace sangramiento digestivo profuso que le lleva a la anemia aguda y al shock hipovolémico, por lo que se envía de nuestro centro al servicio de Cirugía Pediátrica, donde se interviene de urgencia con el diagnóstico de cavernomatosis de la porta, luego de un postoperatorio tórpido, se recupera y egresa.

Masculine transitional,white,with antecedents of severe respiratory distress at birth who needed a umbilical venous catheterization and prolongued mechanic ventilation in the precocious neonatal stage with a delay in the psychomotor development that appear in this case through vomits and bad quality stool which is interpreted as a EDA of a viral ethiology and that during the course of it cause severe digestive bleeding which carry out an acute anaemia and a hypovolemic shock, that´s why it´s sent from our center to the pediatric surgery service, where he recieve special delivery operation with the diagnosis of Porta´s cavernomatosis, then after a post operated dormancy, he is recovered and depart.