Neurofibromatosis Type 1 Vasculopathy Research Articles

ASSOCIATION OF NF-1 AND MOYAMOYA SYNDROME : CASE REPORT

Neurofibromatosis type 1 (NF-1) is the most prevalent autosomal dominant genetic disorder. NF-1 vasculopathy is a significant complication of the disease. It affects both arterial and venous blood vessels of all sizes. Also Moyamoya syndrome is a cerebral vasculopathy . It is rarely detected with NF-1 in the pediatric group. Herein, we report of a 5 year-old male with NF1 and moyamoya syndrome. A 6-month-old baby boy was brought by his family with the complaint of brown spots on the body. On physical examination, cafe au lait spots on the body, subcutaneous nodule in the occipital area and hypotonicity were found. He was examined considering neurofibromatosis, one of the neurocutaneous diseases. Abdominal ultrasonography, brain MRI, echocardiyography, electroencephalography were normal. There was no pathological evidence in eye examination. In genetic tests, NF1 p.GIn2217 gene was found heterozygous positive. patient was followed up with annual brain MRI. Hamartomatous lesions in left putamen and left thalamus posterior were detected in brain MRI when the patient was two years old. There was no pathological evidence on norological physical excamination. When he was three years old thickening and enhancement of the right optic nerve was found in MRI due to possible optic glioma. Only in the left cerebellar hemisphere, two millimeter-sized hamartomatous lesions in the white matter were found to have newly developed. Both internal carotid arteries (ICA) are thinned from the supraclinoid segment. Middle cerebral artery (MCA) M1 segment on the right and anterior cerebral artery (ACA) A1 segment on the left could not be selected. Many thin collateral vascular structures were selected in these localizations and were found to be significant in terms of Moyamoya disease.Regression was detected in right optic glioma. No predisposing factor was found in the examinations of the patient for thrombosis. Acetyl salicylic acid prophylaxis was started. The patient was taken under neurosurgery follow-up for revascularization surgery. The follow-up and treatment continues. Association of NF-1 and Moyamoya syndrome is rare, but carries a potential risk of clinicoradiological progression. Closed monitoring of children with neurofibromatosis type 1 enables early diagnosis of moyamoya syndrome. Revascularization surgery may effective way to prevent progression of clinical symptoms, but long-term results require close follow-up studies.

Neurofibromatosis type 1 associated with coarctation of the abdominal aorta

Neurofibromatosis type 1 (NF1) is one of the most autosomal dominant genetic disorders. NF1 vasculopathy is a rare complication of NF1 with prevalence up to 6% including aneurysms, arterial stenosis, aorta coarctation and arteriovenous malformations [...]

Ruptured tibial artery in neurofibromatosis type 1: A case report.

IntroductionNeurofibromatosis type 1 (NF-1) or von Recklinghausen's disease, an autosomal dominant genetic disorder, is characterized by a café au lait spot and cutaneous neurofibromas. It typically involves the skin, nerves, bones, muscles, and eyes, and occasionally involves vascular complications and can lead to life-threatening hemorrhage.Case presentationWe present the case of a 77-year-old female with a posterior tibial artery rupture with NF-1. She presented with sudden right lower leg swelling, pain, paresthesia, and paralysis; computed tomography images revealed popliteal artery aneurysm with surrounding hematoma, expanding from the posterior aspect of the knee to the calf. Diagnosed with compartment syndrome, due to a ruptured right popliteal artery aneurysm, she underwent prosthetic replacement of the popliteal aneurysm. Intraoperatively, the fragility of the popliteal artery was noted, although no perforation site was recognized despite the aneurysm; active bleeding originated from the hematoma between the calf muscles. Intraoperative digital subtraction angiography revealed an extravasation at the branch of the posterior tibial artery that was managed by coil embolization of the posterior tibial artery.Clinical discussionAlthough the frequency of NF-1 vasculopathy is unknown, vasculopathy is the second most common cause of mortality in patients with NF-1, after malignancy. The less invasive endovascular approach might be preferable for treating NF-1-related aneurysm. The NF-related vasculopathy lesion sites are diverse, and intraoperative angiography would help confirm the diagnosis.ConclusionNF-1-related vasculopathy may be associated with vascular fragility, and the endovascular approach might be preferable. Endovascular-first approach could have helped in correct diagnosis in the present case.

Neurofibromatosis type-1 with seizures and cerebrovascular malformation: a case study

Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous among humans. Epilepsy is more prevalent in NF1 patients than in the general population. NF1 vasculopathy is also a significant but underrecognized complication of the disease, affecting both arterial and venous blood vessels. Herein, we report a 2 year old female child with seizures and multiple cafe-au-lait spots on the body. The patient was diagnosed with NF1 based on clinical findings and family history. MRI Brain revealed middle cerebral artery dysplasia. Here we discuss diagnostic and treatment challenges and briefly reviews the existing literature.

Spontaneous rupture of the pancreatic arcade artery caused by neurofibromatosis type 1 successfully treated using emergency transcatheter arterial embolization, partial intra-aortic balloon occlusion, and stent graft placement: a case report and review of the literature

BackgroundVascular abnormalities in neurofibromatosis type 1 (NF1) are rare, but are the second leading cause of death in persons with NF1. In NF1 vasculopathy (NF-V), fatal bleeding due to a spontaneous arterial rupture sometimes occurs. Ruptured extracranial arteries in patients with NF1 often involve thoracic vessels, such as the intercostal and subclavian arteries; very few reports exist regarding the abdominal region. Herein, we present the first case of intraperitoneal bleeding due to spontaneous pancreatic arcade artery (PAA) rupture associated with NF1, successfully treated by transcatheter arterial embolization (TAE) combined with stent-graft placement and partial intra-aortic balloon occlusion (IABO).Case presentationA 40-year-old woman complained of back and abdominal pain. Upon admission, her blood pressure was 85/41 mmHg and heart rate was 129 beats/min. Computed tomography (CT) showed large intraperitoneal bleeding due to PAA rupture. After CT scanning, her systolic blood pressure decreased to 50 mmHg. Therefore, we performed emergency TAE with partial IABO. She was treated by TAE of the anterior superior pancreaticoduodenal artery, anterior inferior pancreaticoduodenal artery, and inferior pancreaticoduodenal artery. However, even after TAE, minor extravasation around the superior mesenteric artery continued, and her vital signs remained unstable. Stent-graft placement was selected to stop the haemorrhage, preserving normal blood flow of the superior mesenteric artery trunk. Excellent patency of the stent graft was confirmed on follow-up CT, and she was discharged on postoperative day 56.ConclusionPAA rupture associated with NF1 can be successfully treated by TAE combined with partial intra-aortic balloon occlusion, and stent-graft placement.

Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis

Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) tumor suppressor gene, is a negative regulator of Ras signaling. Patients with mutations in NF1 have a strong predisposition for cardiovascular disease, which contributes to their early mortality. Nf1 heterozygous (Nf1+/−) bone marrow to wild type chimeras and mice with heterozygous recombination of Nf1 in myeloid cells recapitulate many of the vascular phenotypes observed in Nf1+/− mutants. Although these results suggest that macrophages play a central role in NF1 vasculopathy, the underlying mechanisms are currently unknown. In the present study, we employed macrophages isolated from either Nf1+/− or Lysm Cre+/Nf1f/f mice to test the hypothesis that loss of Nf1 stimulates macropinocytosis in macrophages. Scanning electron microscopy and flow cytometry analysis of FITC-dextran internalization demonstrated that loss of Nf1 in macrophages stimulates macropinocytosis. We next utilized various cellular and molecular approaches, pharmacological inhibitors and genetically modified mice to identify the signaling mechanisms mediating macropinocytosis in Nf1-deficient macrophages. Our results indicate that loss of Nf1 stimulates PKCδ-mediated p47phox phosphorylation via RAS activation, leading to increased NADPH oxidase 2 activity, reactive oxygen species generation, membrane ruffling and macropinocytosis. Interestingly, we also found that Nf1-deficient macrophages internalize exosomes derived from angiotensin II-treated endothelial cells via macropinocytosis in vitro and in the peritoneal cavity in vivo. As a result of exosome internalization, Nf1-deficient macrophages polarized toward an inflammatory M1 phenotype and secreted increased levels of proinflammatory cytokines compared to controls. In conclusion, the findings of the present study demonstrate that loss of Nf1 stimulates paracrine endothelial to myeloid cell communication via macropinocytosis, leading to proinflammatory changes in recipient macrophages.

Neurofibromatosis Type 1 Vasculopathy Presenting as Impending Central Retinal Artery Occlusion

Neurofibromatosis Type 1 Vasculopathy Presenting as Impending Central Retinal Artery Occlusion

Neurofibromatosis type 1-associated hypertension secondary to coarctation of the thoracic aorta.

Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen's disease, is an autosomal dominant genetic disorder. NF-I vasculopathy has been used to describe various vascular malformations associated with NF-1. Secondary hypertension related to NF-1 vasculopathy has been reported because of renal artery stenosis, coarctation of the abdominal aorta and other vascular lesions; however, coarctation of the thoracic aorta has seldom been reported. We report the first case, to our knowledge, of isolated coarctation of thoracic aorta in a pregnant female with NF-1. Healthcare providers caring for patients with NF-1 should be aware of associated vascular complications.

Neurofibromin-Deficient Myeloid Cells Are Critical Mediators of Aneurysm Formation In Vivo

Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in the development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown. With the use of an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1(+/-) aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin reduced aneurysm formation in Nf1(+/-) mice. These data provide genetic and pharmacological evidence that Nf1(+/-) myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.

Persistent Hypertension Despite Successful Dilation of a Stenotic Renal Artery in a Boy With Neurofibromatosis Type 1

Hypertension is one of the major complications in neurofibromatosis type 1 (NF1). It is known to be caused by renal artery stenosis or pheochromocytoma. However, more than half of hypertensive patients with NF1 do not have either disorder. We report here on a 13-year-old male with NF1 who had hypertension and a stenosis of the right renal artery associated with elevated renal vein renin on the diseased side. He underwent percutaneous transluminal renal angioplasty. In spite of successful dilation of the artery and normalized renin level, high blood pressure persisted beyond 6 months requiring antihypertensive medication. His wide pulse pressure suggested arterial stiffness due to NF1 vasculopathy. We posit that the cause of hypertension in this patient was considered to be arterial stiffness ascribed to NF1 vasculopathy rather than renal artery stenosis. Increased pulse pressure supports the hypothesis. This marker of arterial stiffness can be assessed non-invasively and should be evaluated routinely in NF1.

Neurofibromatosis Type 1 Complicated by Atypical Coarctation of the Thoracic Aorta

Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic disorder with a prevalence of 1 in 3,000 (0.03%) at birth. Clinical features are café-au-lait macules, intertriginous freckling, dermal neurofibroma, iris hamartoma (Lisch nodules), and learning disability. NF1 vasculopathy is a serious but underrecognized complication involving the cerebrovascular and cardiovascular systems. The incidence of hypertension in patients with NF1 is around 1% and is associated mainly with renal artery stenosis in children. Only a few cases of thoracic aortic coarctation in association with hypertension and neurofibromatosis have been reported. Here we describe the case of a 4-year-old girl who presented with NF1 and hypertension due to atypical coarctation of the thoracic aorta. The diagnosis of coarctation of the thoracic aorta at the Th5-to-Th6 level was made following catheterization with a pressure gradient of 40 mmHg. The patient underwent surgery comprising resection of the coarctation of the thoracic aorta and graft interposition. On the basis of our findings, annual assessment of blood pressure is advised for patients with NF1.

Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans

Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. NF1 patients display diverse clinical manifestations, including vascular disease, which results from neointima formation and vessel occlusion. However, the pathogenesis of NF1 vascular disease remains unclear. Vessel wall homeostasis is maintained by complex interactions between vascular and bone marrow-derived cells (BMDCs), and neurofibromin regulates the function of each cell type. Therefore, utilizing cre/lox techniques and hematopoietic stem cell transplantation to delete 1 allele of Nf1 in endothelial cells, vascular smooth muscle cells, and BMDCs alone, we determined which cell lineage is critical for neointima formation in vivo in mice. Here we demonstrate that heterozygous inactivation of Nf1 in BMDCs alone was necessary and sufficient for neointima formation after vascular injury and provide evidence of vascular inflammation in Nf1+/- mice. Further, analysis of peripheral blood from NF1 patients without overt vascular disease revealed increased concentrations of inflammatory cells and cytokines previously linked to vascular inflammation and vasoocclusive disease. These data provide genetic and cellular evidence of vascular inflammation in NF1 patients and Nf1+/- mice and provide a framework for understanding the pathogenesis of NF1 vasculopathy and potential therapeutic and diagnostic interventions.

Extracranial vertebral artery involvement in neurofibromatosis type I. Report of four cases and literature review.

Neurofibromatosis type 1 (NF-1) is one of the most common inherited diseases and as an autosomal dominant genetic disorder results from NF-1 gene mutation with 100% penetration and wide phenotypic variability. The disease can involve a wide variety of tissues derived from all three embryonic layers. NF-1 vasculopathy has been described primarily in peripheral arteries, but arteries supplying the CNS may also be involved. Of those, extracranial vertebral involvement is the commonest and most important. A series of four patients with NF-1 and vascular disease of the vertebral artery is described with a review of the pathophysiology, vascular phenotypes, their management and the pertinent literature.

Is Pulmonary Arterial Hypertension in Neurofibromatosis Type 1 Secondary to a Plexogenic Arteriopathy?

Neurofibromatosis type 1 (NF1) is a common disorder of dysregulated tissue growth secondary to mutations in the tumor suppressor gene NF1. Pulmonary arterial hypertension (PAH) in patients with NF1 is hypothesized to be secondary to an underlying vasculopathy. We describe the entity we term NF1-associated PAH (NF1-PAH) in four new patients and update the data on four previously published reports of patients with PAH and NF1. We performed genetic testing of the bone morphogenic protein receptor 2 (BMPR2) gene, which mutated in 70% of patients with familial PAH and approximately 25% of patients with idiopathic PAH. We report, for the first time, pathologic findings in the autopsy-obtained lung of one patient with NF1-PAH. Patients with NF1-PAH have a generally poor long-term prognosis. In four patients, we observed the mosaic pattern of lung attenuation on a CT scan of the chest, a radiographic finding that can be consistent with an underlying vasculopathy. No mutations or rearrangements in the BMPR2 gene were found. We observed complex plexiform lesions in the one available autopsy specimen. Similar lesions are a hallmark of plexogenic pulmonary arteriopathy and are associated with several severe types of PAH. (Plexiform lesions should not be confused with plexiform neurofibromas, which are distinctive tumors seen in NF1.) Our findings suggest that NF1 should be considered as being "associated with PAH as outlined in the Revised Clinical Classification of Pulmonary Hypertension. Understanding the mechanism of PAH in NF1 may inform the pathogenesis of PAH, NF1-PAH itself, and other NF1-associated vasculopathies. The pulmonary vasculature should now be included among the arterial beds affected by NF1 vasculopathy.

Hypoglossal-Facial Anastomosis

Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) tumor suppressor gene, is a negative regulator of Ras signaling. Patients with mutations in NF1 have a strong predisposition for cardiovascular disease, which contributes to their early mortality. Nf1 heterozygous (Nf1+/−) bone marrow to wild type chimeras and mice with heterozygous recombination of Nf1 in myeloid cells recapitulate many of the vascular phenotypes observed in Nf1+/− mutants. Although these results suggest that macrophages play a central role in NF1 vasculopathy, the underlying mechanisms are currently unknown. In the present study, we employed macrophages isolated from either Nf1+/− or Lysm Cre+/Nf1f/f mice to test the hypothesis that loss of Nf1 stimulates macropinocytosis in macrophages. Scanning electron microscopy and flow cytometry analysis of FITC-dextran internalization demonstrated that loss of Nf1 in macrophages stimulates macropinocytosis. We next utilized various cellular and molecular approaches, pharmacological inhibitors and genetically modified mice to identify the signaling mechanisms mediating macropinocytosis in Nf1-deficient macrophages. Our results indicate that loss of Nf1 stimulates PKCδ-mediated p47phox phosphorylation via RAS activation, leading to increased NADPH oxidase 2 activity, reactive oxygen species generation, membrane ruffling and macropinocytosis. Interestingly, we also found that Nf1-deficient macrophages internalize exosomes derived from angiotensin II-treated endothelial cells via macropinocytosis in vitro and in the peritoneal cavity in vivo. As a result of exosome internalization, Nf1-deficient macrophages polarized toward an inflammatory M1 phenotype and secreted increased levels of proinflammatory cytokines compared to controls. In conclusion, the findings of the present study demonstrate that loss of Nf1 stimulates paracrine endothelial to myeloid cell communication via macropinocytosis, leading to proinflammatory changes in recipient macrophages.