Internal plexiform neurofibromas are a major cause of adverse outcomes in patients with neurofibromatosis 1 (NF1). We investigated the relationship of the numbers of subcutaneous neurofibromas of the scalp or body to internal plexiform tumor volume in 120 NF1 patients who had undergone whole body magnetic resonance imaging (MRI). We identified internal plexiform neurofibromas in 55% of patients, subcutaneous neurofibromas of the body in 75%, and subcutaneous neurofibromas of the scalp in 45%. The number of subcutaneous neurofibromas of the body and scalp were associated with each other (Spearman's Rho = 0.36; P < 0.001). The presence of internal tumors was associated with the presence (odds ratio [OR] = 4.38, 95% confidence interval [CI] 2.04-9.86, P < 0.001) and number (OR = 1.06 per neurofibroma, 95% CI 1.02-1.13, P < 0.001) of subcutaneous neurofibromas of the scalp. The total internal tumor volume was associated with the number of subcutaneous neurofibromas of the body (OR = 1.00086 per neurofibroma, 1.000089-1.0016, P = 0.029) and of the scalp (OR = 1.056 per neurofibroma, 1.029-1.083, P < 0.0001). Numbers of subcutaneous neurofibromas of the scalp and body are associated with internal plexiform tumor burden in NF1. Recognition of these associations may improve clinical management by helping to identify patients who will benefit most from whole body MRI and more intense clinical surveillance.
The fertility of men with neurofibromatosis 1 (NF1) is reduced. Despite this observation, gonadal function has not been examined in patients with NF1. In order to assess the role of reduced neurofibromin in the testes, we examined testicular morphology and function in an Nf1+/- mouse model. We found that although Nf1+/- male mice are able to reproduce, they have significantly fewer pups per litter than Nf1+/+ control males. Reduced fertility in Nf1+/- male mice is associated with disorganization of the seminiferous epithelium, with exfoliation of germ cells and immature spermatids into the tubule lumen. Morphometric analysis shows that these alterations are associated with decreased Leydig cell numbers and increased spermatid cell numbers. We hypothesized that hyper-activation of Ras in Nf1+/- males affects ectoplasmic specialization, a Sertoli-spermatid adherens junction involved in spermiation. Consistent with this idea, we found increased expression of phosphorylated ERK, a downstream effector of Ras that has been shown to alter ectoplasmic specialization, in Nf1+/- males in comparison to control Nf1+/+ littermates. These data demonstrate that neurofibromin haploinsufficiency impairs spermatogenesis and fertility in a mouse model of NF1.
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder presented with multiple café‐au‐lait spots, Lisch nodules,multiple nerve sheath tumors, and cardiovascular complications such as ischemia or aneurysm. Multiple vessels are affected in NF1 patients, but the abdominal aorta (AA) and renal arteries (RA) are most commonly reported, even though, the pathogenesis is not well understood. In this study, we examined functions of the AA and RA in a mouse model of NF1. We report a decrease in contraction and an increase in relaxation of smooth muscle cells (SMCs) in both the AA and RA at the age of 6 months. The nitric oxide synthase inhibitor (L‐NAME) completely blocked SMCs relaxation, indicating that the alterations resulted from enhanced nitric oxide (NO) production. The constitutional production of NO may reduce the availability of cofactors required for endothelial NOS to function. To determine if the increased production of NO had caused further dysfunction over time, we examined the AA in 9‐12 month old mice. Interestingly, we observed increased contraction and reduced relaxation in 9‐12 month old Nf1+/‐mice compared to controls, which may be indicative of a further decrease in NO bio‐availability. Taken together, our data demonstrates that underlying changes in SMCs and the endothelium contribute to vascular complications in NF1, providing new insights on potential future therapeutic approaches to address vascular complications in these patients. This study was funded by the British Columbia Neurofibromatosis Foundation and the Children's Tumor Foundation.
Neurofibromatosis 1 (NF1) is an autosomal dominant disorder, characterized by multiple café‐au‐lait spots, iris harmartomas, multiple nerve sheath tumors. Patients also present with heart and cerebrovascular disease, ischemia, or aneurysm. Though vasculopathy is well documented in NF1 patients, the pathophysiology is poorly understood. The objective of this study was to investigate the function and structural integrity of the thoracic aorta in a well‐established mouse model of NF1 (6‐month old). We observed a significant increase in contraction in response to depolarization of vascular smooth muscle and endothelial cells in Nf1+/‐ mice, but diminished contraction in response to phenylephrine. Interestingly, endothelium‐dependent relaxation was significantly higher in Nf1+/‐ mice, which was completely inhibited by the nitric oxide synthase (NOS) inhibitor, suggesting the relaxation results from nitric oxide (NO) production. Consistent with increased NO production, protein expression of endothelial NOS (eNOS), phospho‐eNOS, and the phospho‐Akt were increased in Nf1+/‐ aorta. Histological examination revealed that alteration in aortic function is also associated with elastin fiber disorganization within the aortic wall. This study, for the first time, underscores the pathological events underlying vascular complications in NF1, shedding light on potential new therapeutic targets to address vascular dysfunctions in NF1 patients. The presented study was funded by the Children's Tumor Foundation and the Canadian Institutes of Health Research.
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