Manifestations Of NF1 Research Articles

Breast cancer associated with type 1 neurofibromatosis

The association between breast cancer and type 1 neurofibromatosis (NF1) is a rare clinical entity. We herein present the case of a 59-year-old woman, with typical clinical manifestations of NF1, who presented with a painless lump in her right breast, which she had first noticed 8 months earlier. Clinical examination and diagnostic workup were suggestive of a breast carcinoma, and a modified radical mastectomy was performed. Histopathological examination revealed a poorly differentiated invasive ductal breast carcinoma and multiple neurofibromas. The pathological staging was pT2N1a according to TNM/UICC. Delayed presentation of the patient was the result of her mistakenly identifying the breast tumor as a manifestation of NF1 neurofibromatosis.

Nf1+/- mice have increased neointima formation via hyperactivation of a Gleevec sensitive molecular pathway

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the NF1 tumor suppressor gene. Neurofibromin is encoded by NF1 and functions as a negative regulator of Ras activity. Somatic mutations in the residual normal NF1 allele within cancers of NF1 patients is consistent with NF1 functioning as a tumor-suppressor. However, the prevalent non-malignant manifestations of NF1, including learning and bone disorders emphasize the importance of dissecting the cellular and biochemical effects of NF1 haploinsufficiency in multiple cell lineages. One of the least studied complications of NF1 involves cardiovascular disorders, including arterial occlusions that result in cerebral and visceral infarcts. NF1 vasculopathy is characterized by vascular smooth muscle cell (VSMC) accumulation in the intima area of vessels resulting in lumen occlusion. We recently showed that Nf1 haploinsufficiency increases VSMC proliferation and migration via hyperactivation of the Ras-Erk pathway, which is a signaling axis directly linked to neointima formation in diverse animal models of vasculopathy. Given this observation, we tested whether heterozygosity of Nf1 would lead to vaso-occlusive disease in genetically engineered mice in vivo. Strikingly, Nf1+/- mice have increased neointima formation, excessive vessel wall cell proliferation and Erk activation after vascular injury in vivo. Further, this effect is directly dependent on a Gleevec sensitive molecular pathway. Therefore, these studies establish an Nf1 model of vasculopathy, which mirrors features of human NF1 vaso-occlusive disease, identifies a potential therapeutic target and provides a platform to further dissect the effect of Nf1 haploinsufficiency in cardiovascular disease.

NF1 tumor suppressor protein and mRNA in skeletal tissues of developing and adult normal mouse and NF1-deficient embryos.

NF1 is a heritable disease with multiple osseous lesions. The expression of the NF1 gene was studied in embryonic and adult rodent skeleton and in NF1-deficient embryos. The NF1 gene was expressed intensely in the cartilage and the periosteum. Impaired NF1 expression may lead to inappropriate development and dynamics of bones and ultimately to the osseous manifestations of the disease. Neurofibromatosis type 1 is caused by mutations in the NF1 gene encoding the Ras GTPase activating protein (Ras-GAP) neurofibromin. Skeletal ailments such as short stature, kyphoscoliosis, and tibial bowing and pseudarthrosis are common osseous manifestations of NF1. These symptoms are congenital, implying a role for neurofibromin in proper bone growth. However, little is known about its expression in skeletal tissues during their development. The expression of the NF1 gene was studied in normal and NF1+/- mouse fetuses at embryonic days 12.5-15.5 and in skeletal tissues of adult mice and rats. In situ hybridization, immunohistochemistry, and Western blot analysis were used to identify the NF1 gene expression profile. NF1 mRNA and protein were elevated in resting, maturation, and hypertrophic chondrocytes at the growth plate. Parallel studies on NF1+/- embryos showed expression patterns identical to wildtype. The periosteum, including osteoblasts and osteoclasts, and osteocytes of the cortical bone of adult mice were also intensely labeled for NF1 protein and mRNA. Western transfer analysis detected NF1 protein in the respective rat tissues. Phosphorylation of p42 and p44 MAP kinases, the downstream consequence of Ras activation, was elevated in hypertrophic chondrocytes of NF1+/- embryos. The results suggest that neurofibromin may act as a Ras-GAP in skeletal cells to attenuate Ras transduced growth signals and thus play a role during ossification and dynamics of bone. Loss of NF1 function may therefore lead to dysplastic bone growth, thereby causing the debilitating osseous symptoms of NF1.

Clinical manifestations of NF1 in African-Americans and Caucasians

Most of the clinical manifestations of NF1 are thought to occur in similar frequencies in different ethnic groups. One exception to this assumption may be optic glioma, which has been reported to be less common in African-Americans. We have compared the manifestations of NF1 in a retrospective analysis of 55 individuals with NF1, including 39 Caucasians and 16 African-Americans in the first part of the study. All patients met the NIH consensus criteria for NF1. The diagnosis of NF1 was established at the mean age of 11.1 years in African-Americans and 8.3 years in Caucasians (±SD 6.9 years for African-Americans and 12.3 years for Caucasians; p<0.01). The results revealed that most of the findings were seen in similar frequencies in African-Americans and Caucasians. However, the following manifestations were found to be different: 3 of 16 African-Americans and 3 of 39 Caucasians were noted to have plexiform neuroma. None of the African-Americans were found to develop renal artery stenosis, although it was noted in 2 Caucasians. Three patients from the African-American group were found to develop intracranial tumors other than optic glioma, although none of the Caucasians were noted to have similar tumors in our sample. One explanation for these differences would be that African-Americans might be getting medical attention only if they have significant problems such as plexiform neuroma or intracranial tumors. To better evaluate the previously reported difference on the frequency of optic glioma, we are collecting a larger sample currently including 84 African-Americans and 880 Caucasians. Thus far optic glioma has been diagnosed in 4 of the 84 (4.8%) patients whose both parents were African-Americans and in 144 of the 880 (16.4%) Caucasians (further analysis is continuing). Our results thus far suggest that the manifestations of NF-1 are somewhat different in African-Americans, a lower frequency of optic glioma being the most significant difference. Better understanding of clinical differences in patients with NF-1 from different ethnic groups will help to identify modifying genetic factors and to establish appropriate individualized diagnostic and management plans.

Behavioral phenotype of neurofibromatosis, type 1.

Neurofibromatosis, type 1 (NF1) is a very common inherited disorder that was first described in the late 19th century. NF1 is associated with a myriad of behavioral manifestations in addition to its frequent and often severe medical and physical complications. Learning disability, cognitive impairment, emotional and psychosocial difficulties have been reported so frequently in neurofibromatosis that these are often considered hallmarks. This report briefly introduces the medical and physical characteristics of NF1. We then detail the behavioral manifestations of NF1 with additional discussion of possible etiologies for the high incidence of these behavioral difficulties. MRDD Research Reviews 2000;6:117-124.

Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients

Type 1 Neurofibromatosis, NF1, is a common genetic disorder with variable clinical manifestations. Although NF1 often is only of cosmetic concern, serious and even lethal complications may occur. It is not possible to predict which symptoms will develop in any affected individual. The NNFF International Database is a multicentre collaborative system for collecting information about this condition. At the time of this analysis, complete clinical information was available on 1,479 probands and 249 of their affected relatives with NF1. On average, the age at diagnosis of NF1 was 8 years younger in the probands than in the affected relatives (P<.01). Many of the manifestations of NF1 were more frequent in the probands than in their affected relatives. The age-specific prevalence of most manifestations of NF1 increases with age. Despite biases inherent in a convenience sample from specialist clinics, the frequencies of many of the serious manifestations of NF1 are similar to those of two smaller population-based studies. The frequencies in this study are likely representative of patients seen at specialized clinics.

Blindness, deafness, quadriparesis, and a retinal malformation: the ravages of neurofibromatosis 2

Advances in molecular biology have established that the diseases once collectively referred to as neurofibromatosis are actually genetically distinct and clinically heterogeneous conditions. This realization has led to separate definitions for neurofibromatosis (NF) type 1 and 2. Although ophthalmologic manifestations of NF1 have long been recognized, the distinguishing ocular features of NF2 have only recently received attention. We describe an inferior retinopapillary malformation with an overlying glial hamartoma in a deaf, quadriparetic patient with NF2. Magnetic resonance (MR) imaging initially showed bilateral vestibular schwannomas and a large cervical ependymoma. Over six years of follow-up, the patient developed multiple intracranial meningiomas.

Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons

NF1 patients display CNS abnormalities including learning disabilities, clumsiness, astrocytomas, and abnormalities on magnetic resonance imaging exams. To determine whether the cellular and neuroanatomical distribution of neurofibromin reveals possible function for neurofibromin in the brain, we stained rat brain tissue sections with anti-neurofibromin antibodies. Neurofibromin is highly enriched in large projection neurons, such as cortical and hippocampal pyramidal cells and cerebellar Purkinje cells. Neurofibromin is present in cell bodies and in axons, but is highly enriched in dendrites. Immunoelectron microscopic analysis demonstrates that NF1 is associated with smooth vesiculotubular elements and cisternal stacks and with multivesicular bodies in the cell body and dendrites, but not with the plasma membrane, nucleus, nuclear envelope, Golgi apparatus, mitochondria, or rough endoplasmic reticulum. The preferential localization of neurofibromin to the smooth endoplasmic reticulum, together with evidence that neurofibromin modulates ras GTPase activity, suggests that some, if not all, of the CNS manifestations of NF1 might result from the altered expression of neurofibromin in neurons, perhaps through disruption of Ca2+ signaling, translocation of organelles, or endocytic pathways.