RESUMEN
Gain of function PIK3CA pathogenic variants have been identified in overgrowth syndromes collectively termed "PIK3CA-related overgrowth spectrum" (PROS). There are no previously reported cases of cerebrovascular venous malformations in PROS syndromes, though somatic activating PIK3CA variants have been identified in extracranial venous malformation. This study was approved by the Institutional Review Boar at Boston Children's Hospital. A 14-year-old female mosaic for the de novo p.R108H pathogenic variant in the PIK3CA gene was found to have a large tumor involving the superior sagittal sinus with mass effect on the motor cortex most consistent with a parafalcine meningioma. She underwent surgical resection with pathology demonstrating a venous malformation. PIK3CA pathogenic variants have been identified in nonsyndromic extracranial venous and lymphatic malformations as well in brain tumors, including glioma and meningioma. However, PIK3CA variants have not previously been identified in purely intracranial venous malformations. This distinction is relevant to treatment decisions, given that mTOR inhibitors may provide an alternative option for noninvasive therapy in cases of suspected venous malformation.
Asunto(s)
Neoplasias Meníngeas , Meningioma , Malformaciones Vasculares , Adolescente , Animales , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Meningioma/diagnóstico , Meningioma/genética , Mutación , Síndrome , Factores de Transcripción/genética , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/genéticaAsunto(s)
Ciclina D2/genética , Predisposición Genética a la Enfermedad , Hidrocefalia/genética , Malformaciones del Desarrollo Cortical/genética , Meduloblastoma/genética , Polidactilia/genética , Femenino , Humanos , Hidrocefalia/complicaciones , Hidrocefalia/patología , Lactante , Malformaciones del Desarrollo Cortical/complicaciones , Malformaciones del Desarrollo Cortical/patología , Meduloblastoma/complicaciones , Meduloblastoma/patología , Polidactilia/complicaciones , Polidactilia/patologíaRESUMEN
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.
Asunto(s)
Enfermedades Vasculares , Malformaciones de la Vena de Galeno , Humanos , Animales , Ratones , Malformaciones de la Vena de Galeno/genética , Malformaciones de la Vena de Galeno/patología , Células Endoteliales/patología , Mutación , Transducción de Señal/genética , Mutación Missense , Proteínas Activadoras de GTPasa/genética , Receptores de Activinas Tipo II/genética , Proteína Activadora de GTPasa p120/genéticaRESUMEN
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP ( RASA1 ) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79×10 -7 ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 ( EPHB4 ) (p=1.22×10 -5 ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1 , NOTCH1 , ITGB1 , and PTPN11 . ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.
RESUMEN
We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2:EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p < 0.05, respectively). EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients. Using the optimal urinary cutoff value (EphrinB2 > 25.7 pg/µg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Post-treatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target.
Asunto(s)
Biomarcadores , Células Endoteliales/metabolismo , Efrina-B2/genética , Malformaciones Arteriovenosas Intracraneales/diagnóstico , Malformaciones Arteriovenosas Intracraneales/etiología , Receptor EphB4/genética , Células Cultivadas , Niño , Efrina-B2/metabolismo , Expresión Génica , Humanos , Malformaciones Arteriovenosas Intracraneales/metabolismo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Curva ROC , Receptor EphB4/metabolismoRESUMEN
The literature has long attempted distinct classifications of arteriovenous fistulae and arteriovenous malformations of the spine.1-3 It is worth noting that lesions can become more complex during recurrence and may not adhere to traditional definitions. In these cases, recognizing the principles of pathology and pathophysiology can guide management and treatment. We present the case of a spinal arteriovenous malformation with recurrence after prior treatment that is managed in the setting of a second opinion with a multidisciplinary approach. This case demonstrates (1) an evolution of recurrent arteriovenous shunting pathology observed both in the endovascular suite, and under direct microscopic visualization and (2) considerations in multimodal treatment with endovascular devices during microsurgical dissection and extirpation. This manuscript was prepared with informed assent provided by the patient (a minor) and with informed consent by the parent of the patient, who is their legal representative and health-care proxy.