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Sample records for neurofibromatosis nf1 intra

  1. Neurofibromatosis type 1 (NF1) and associated tumors.

    Science.gov (United States)

    Rosenbaum, T; Wimmer, K

    2014-11-01

    Neurofibromatosis type 1 (NF1) is a frequent neurocutaneous syndrome that predisposes for various benign and malignant tumors. Most characteristic are neurofibromas which occur in almost all NF1 patients at some point in lifetime. Although neurofibromas are benign tumors they can be disfiguring and plexiform neurofibromas may progress to malignant peripheral nerve sheath tumors. Overall survival rates of patients with these malignant tumors are poor. Other neoplasias frequently observed in NF1 patients are pilocytic astrocytomas, gastrointestinal stromal tumors, pheochromocytomas and juvenile myelomonocytic leukemia. Several other tumors have been reported in NF1 patients but it is unclear if there is a true association between the particular tumor type and NF1. Some of these tumors might be caused by a rare recessively inherited childhood cancer syndrome termed constitutive mismatch repair deficiency syndrome which shows certain phenotypic overlap with NF1 but includes a broad spectrum of tumors which usually do not occur in NF1. The development of NF1-associated tumors is largely explained by the underlying defect of the NF1 gene which results in activation of the RAS proto-oncogene- a key mechanism of tumorigenesis. Several downstream effectors of activated RAS as well as cooperating molecular pathways have been identified. These insights provide the basis to develop novel targeted treatment strategies which are urgently needed to improve the outcome for patients with NF1-associated malignancies.

  2. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.

    Science.gov (United States)

    Gutmann, David H; McLellan, Michael D; Hussain, Ibrahim; Wallis, John W; Fulton, Lucinda L; Fulton, Robert S; Magrini, Vincent; Demeter, Ryan; Wylie, Todd; Kandoth, Cyriac; Leonard, Jeffrey R; Guha, Abhijit; Miller, Christopher A; Ding, Li; Mardis, Elaine R

    2013-03-01

    Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.

  3. Spinal neurofibromatosis in a family with classical neurofibromatosis type 1 and a novel NF1 gene mutation.

    Science.gov (United States)

    Nicita, Francesco; Torrente, Isabella; Spalice, Alberto; Bottillo, Irene; Papetti, Laura; Pinna, Valentina; Ursitti, Fabiana; Ruggieri, Martino

    2014-02-01

    Familial spinal neurofibromatosis (FSNF) is a rare form of neurofibromatosis type 1 (NF1) characterized by multiple, histologically proven neurofibromas of the spinal roots leaving no intact segments and associated neurofibromas of major peripheral nerves. It is sometimes associated with other NF1 stigmata. Most patients have NF1 gene mutations. We describe a patient who fulfilled the diagnostic criteria for spinal neurofibromatosis and belonged to a family in which other affected members exhibited classical NF1 stigmata. A novel missense (c.7109 T>A; p.Val2370Asp) mutation in exon 39 of the NF1 gene was present in the affected family members. The family displayed extreme phenotypic variability in the spectrum of NF1. To our knowledge, this is the first patient with spinal neurofibromatosis in the context of classical NF1 with an NF1 gene mutation. The term FSNF is inaccurate as this condition simply reflects the typical autosomal dominant pattern of NF1 inheritance with phenotypoc variability and does not encompass patients with sporadic disease or those in the context of a classical NF1 phenotype as reported in the present family. The term could be replaced by "spinal neurofibromatosis".

  4. The Spectrum of NF1 Mutations in Korean Patients with Neurofibromatosis Type 1

    OpenAIRE

    Jeong, Seon-Yong; Park, Sang-Jin; Kim, Hyon J.

    2006-01-01

    Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations in the NF1 gene which consists of 57 exons and encodes a GTPase activating protein (GAP), neurofibromin. To date, more than 640 different NF1 mutations have been identified and registered in the Human Gene Mutation Database (HGMD). In order to assess the NF1 mutational spectrum in Korean NF1 patients, we screened 23 unrelated Korean NF1 patients for mutations in the codi...

  5. Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient.

    Science.gov (United States)

    Emmerich, Denise; Zemojtel, Tomasz; Hecht, Jochen; Krawitz, Peter; Spielmann, Malte; Kühnisch, Jirko; Kobus, Karolina; Osswald, Monika; Heinrich, Verena; Berlien, Peter; Müller, Ute; Mautner, Victor-F; Wimmer, Katharina; Robinson, Peter N; Vingron, Martin; Tinschert, Sigrid; Mundlos, Stefan; Kolanczyk, Mateusz

    2015-06-01

    Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G>A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors.

  6. Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion.

    Science.gov (United States)

    Pizzuti, Antonio; Bottillo, Irene; Inzana, Francesca; Lanari, Valentina; Buttarelli, Francesca; Torrente, Isabella; Giallonardo, Anna Teresa; De Luca, Alessandro; Dallapiccola, Bruno

    2011-08-01

    We report the detailed clinical presentation and molecular features of a spinal neurofibromatosis familial case where a 40-year-old woman, presenting with multiple bilateral spinal neurofibromas and no other clinical feature of neurofibromatosis type 1 (NF1), inherited a paternal large multiexonic deletion (c.5944-?_7126+?del) which resulted in NF1 gene haploinsufficiency at the RNA level. In the clinically unaffected 73-year-old father, spinal cord MRI disclosed bilateral and symmetrical hypertrophy of spinal lumbosacral roots. Our study widens the phenotypic and mutational spectrum of NF1 and illustrates the difficulties of counseling patients with border-line or atypical presentation of this disorder.

  7. Neurofibromatosis

    Science.gov (United States)

    ... out of control and form tumors. What is NF1? NF1 is the most common neurofibromatosis, occurring in ... generations. What are the signs and symptoms of NF1? To diagnose NF1, a doctor looks for two ...

  8. Fused teeth, macrodontia and increased caries are characteristic features of neurofibromatosis type 1 patients with NF1 gene microdeletion

    OpenAIRE

    Kobayashi, Ryosuke; Matsune, Kensuke; Ohashi, Hirofumi

    2012-01-01

    Neurofibromatosis type 1 (NF1) is the most common genetic condition caused by NF1 gene alteration. A 1.5 Mb submicroscopic deletion encompassing the entire NF1 gene, is known to be responsible for approximately 5% of NF1 cases. Patients with NF1 deletion, compared to those with NF1 mutation tend to exhibit more severe phenotypes. To know the possible differences in oral/dental features between NF1 deletion and NF1 mutation patients, we examined four patients with NF1 deletion and three with N...

  9. Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas.

    Science.gov (United States)

    Peltonen, Sirkku; Kallionpää, Roope A; Peltonen, Juha

    2016-09-13

    Neurofibromatosis 1 (NF1) occurs in 1:2000 births. The main diagnostic signs are visible on the skin, and this opens several interesting aspects for dermatological point of view. The NF1 syndrome is caused by mutations in the NF1 gene which encodes the tumor suppressor protein neurofibromin. Neurofibromin functions as a Ras-GTPase-activating protein (RasGAP), and NF1 mutations lead to overactivation of the Ras signalling pathway. The NF1 gene and neurofibromin have intriguing functions in keratinocytes and melanocytes. Neurofibromin regulates melanin synthesis and keratinocyte differentiation in a currently unknown manner. The NF1 gene has also an important but poorly understood role in tumorigenesis and cancer. Compared to the general population, NF1 patients have a fivefold risk for cancer and a more than 2000-fold risk for neurogenic malignancies. Mutations of the NF1 gene are common in numerous cancer types in patients without NF1, and this suggests a more general role for the NF1 gene in oncogenesis. In melanoma, NF1 mutations seem to drive tumorigenesis and contribute to drug resistance. In this article, we review the literature on neurofibromin with special attention to keratinocytes, melanocytes, NF1-related tumors and melanoma.

  10. NF1 single and multi-exons copy number variations in neurofibromatosis type 1.

    Science.gov (United States)

    Imbard, Apolline; Pasmant, Eric; Sabbagh, Audrey; Luscan, Armelle; Soares, Magali; Goussard, Philippe; Blanché, Hélène; Laurendeau, Ingrid; Ferkal, Salah; Vidaud, Michel; Pinson, Stéphane; Bellanne-Chantelot, Christine; Vidaud, Dominique; Wolkenstein, Pierre; Parfait, Béatrice

    2015-04-01

    Neurofibromatosis type 1 (NF1) is caused by dominant loss-of-function mutations of the tumor suppressor NF1 containing 57 constitutive coding exons. A huge number of different pathogenic NF1 alterations has been reported. The aim of the present study was to evaluate the usefulness of a multiplex ligation-dependent probe amplification (MLPA) approach in NF1 patients to detect single and multi-exon NF1 gene copy number variations. A genotype-phenotype correlation was then performed in NF1 patients carrying these types of genetic alterations. Among 565 NF1 index cases from the French NF1 cohort, single and multi-exon deletions/duplications screening identified NF1 partial deletions/duplications in 22 patients (~4%) using MLPA analysis. Eight single exon deletions, 11 multiple exons deletions, 1 complex rearrangement and 2 duplications were identified. All results were confirmed using a custom array-CGH. MLPA and custom array-CGH allowed the identification of rearrangements that were missed by cDNA/DNA sequencing or microsatellite analysis. We then performed a targeted next-generation sequencing of NF1 that allowed confirmation of all 22 rearrangements. No clear genotype-phenotype correlations were found for the most clinically significant disease features of NF1 in patients with single and multi-exons NF1 gene copy number changes.

  11. Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis

    Science.gov (United States)

    Kresak, Jesse Lee; Walsh, Meggen

    2016-01-01

    The neurofibromatoses are a heterogeneous group of hereditary cancer syndromes that lead to tumors of the central and peripheral nervous systems, as well as other organ systems. By far the most common form is neurofibromatosis 1 (96%), followed by neurofibromatosis 2 (3%), and a more recently recognized, lesser known form, schwannomatosis. The diagnostic criteria, pathogenesis, molecular considerations, and clinical manifestations are discussed in this review article. PMID:27617150

  12. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.

    Science.gov (United States)

    Sabbagh, Audrey; Pasmant, Eric; Imbard, Apolline; Luscan, Armelle; Soares, Magali; Blanché, Hélène; Laurendeau, Ingrid; Ferkal, Salah; Vidaud, Michel; Pinson, Stéphane; Bellanné-Chantelot, Christine; Vidaud, Dominique; Parfait, Béatrice; Wolkenstein, Pierre

    2013-11-01

    Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant-related patients. A genotype-phenotype study was performed in patients harboring a truncating (N = 368), in-frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity.

  13. Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas

    Science.gov (United States)

    2013-07-01

    Mesylate (STI-571, NSC 716051) In Neurofibromatosis ( NF1 ) Patients with Plexiform Neurofibromas PRINCIPAL INVESTIGATOR: Kent Robertson, M.D...Imatinib Mesylate (STI-571, NSC 716051) In Neurofibromatosis ( NF1 ) Patients with Plexiform Neurofibromas 5b. GRANT NUMBER W81XWH-09-1-0120 5c. PROGRAM...Section I - Introduction of research The goal of this Pilot Study is to trial multiple techniques for determining the response of NF1 patients with

  14. Lack of NF1 gene expression in a sporadic schwannoma from a patient without neurofibromatosis

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    Norton, K.K.; Dowton, B. [St. Louis Childrens Hospital, MO (United States); Silow-Santiago, I. [Washington Univ. School of Medicine, St. Louis, MO (United States)] [and others

    1994-09-01

    The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, neurofibromin, which is expressed at high levels in Schwann cells and other adult tissues. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 and its loss is associated with increased proliferation of these cells. We examined one spinal schwannoma from a patient without clinical features of neurofibromatosis type 1 or 2. The tumor was a typical schwannoma confirmed by standard neuropathologic criteria and expressed S100 by immunocytochemistry. NF1 gene expression in this tumor was examined by in situ hybridization using an NF1-specific riboprobe, Northern blot analysis and reverse-transcribed (RT) PCR. Little or no expression of NF1 RNA could be detected using these methods whereas abundant expression of S100, cyclophilin and beta-action RNA was found in the tumor. Fibroblast and Schwann cells were then individually cultured from this schwannoma and the RNA extracted for Northern blot and RT-PCR analysis. In these cultured Schwann cells both from early and late passages, abundant expression of NF1 RNA could be detected. It is unlikely that our culture technique preferentially expanded {open_quotes}normal{close_quotes} Schwann cells, since NF1 acts as a tumor suppressor gene and its presence would not confer any growth advantage over the tumor-derived, neurofibromin-negative Schwann cells which presumably have an increased proliferation rate. Similarly, the conditions used to expand these Schwann cells do not result in increased NF1 gene expression as shown in previous studies. These results suggest that, in some tumors, expression of the NF1 gene can be downregulated by factors produced within the tumor and that this type of tumor suppressor gene downregulation may represent another mechanism other than mutation for turning off the expression of these growth-suppressing genes and allowing for cell proliferation in tumors.

  15. Identification and characterization of NF1 splicing mutations in Korean patients with neurofibromatosis type 1.

    Science.gov (United States)

    Jang, Mi-Ae; Kim, Young-Eun; Kim, Sun Kyung; Lee, Myoung-Keun; Kim, Jong-Won; Ki, Chang-Seok

    2016-08-01

    Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder caused by NF1 mutations. Although mutations affecting mRNA splicing are the most common molecular defects in NF1, few studies have analyzed genomic DNA (gDNA)-mRNA correlations in Korean NF1 patients. In this study, we investigated 28 unrelated NF1 patients who showed splicing alterations in reverse transcription-PCR of NF1 mRNA and identified 24 different NF1 splicing mutations, 9 of which were novel. These mutations can be categorized into five groups: exon skipping resulting from mutations at authentic 5' and 3' splice sites (type I, 46%), cryptic exon inclusion caused by deep intronic mutations (type II, 8%), creation of new splice sites causing loss of exonic sequences (type III, 8%), activation of cryptic splice sites due to disruption of authentic splice sites (type IV, 25%) and exonic sequence alterations causing exon skipping (type V, 13%). In total, 42% of all splicing mutations did not involve the conserved AG/GT dinucleotides of the splice sites, making it difficult to identify the correct mutation sites at the gDNA level. These results add to the mutational spectrum of NF1 and further elucidate the gDNA-mRNA correlations of NF1 mutations.

  16. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis

    NARCIS (Netherlands)

    B.V. Balgobind (Brian); P. van Vlierberghe (Pieter); A.M.W. van den Ouweland (Ans); H.B. Beverloo (Berna); J.N.R. Terlouw-Kromosoeto (Joan); E.R. van Wering (Elisabeth); D. Reinhardt (Dirk); M.A. Horstmann (Martin); G.J. Kaspers (Gertjan); R. Pieters (Rob); C.M. Zwaan (Christian Michel); M.M. van den Heuvel-Eibrink (Marry); J.P.P. Meijerink (Jules)

    2008-01-01

    textabstractNeurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. Patients with NF1 have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression toward acute myeloid leukemia (AML). In an oligo array compara

  17. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis

    NARCIS (Netherlands)

    Balgobind, Brian V.; Van Vlierberghe, Pieter; van den Ouweland, Ans M. W.; Beverloo, H. Berna; Terlouw-Kromosoeto, Joan N. R.; van Wering, Elisabeth R.; Reinhardt, Dirk; Horstmann, Martin; Kaspers, Gertjan J. L.; Pieters, Rob; Zwaan, C. Michel; Van den Heuvel-Eibrink, Marry M.; Meijerink, Jules P. P.

    2008-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. Patients with NF1 have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression toward acute myeloid leukemia (AML). In an oligo array comparative genomic

  18. Parental age and Neurofibromatosis Type 1: a report from the NF1 Patient Registry Initiative.

    Science.gov (United States)

    Liu, Qian; Zoellner, Nancy; Gutmann, David H; Johnson, Kimberly J

    2015-06-01

    One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95% CI 3.23-5.46, p ≤ 0.0001) and 3.39 years (95% CI 1.57-5.20, p ≤ 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1.

  19. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1.

    Science.gov (United States)

    Toonen, Joseph A; Anastasaki, Corina; Smithson, Laura J; Gianino, Scott M; Li, Kairong; Kesterson, Robert A; Gutmann, David H

    2016-05-01

    Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.2542G>C;p.G848R and c.2041C>T;p.R681X). We found that each germline Nf1 gene mutation resulted in different levels of neurofibromin expression. Importantly, only R681X(CKO) but not G848R(CKO), mice develop optic gliomas with increased optic nerve volumes, glial fibrillary acid protein immunoreactivity, proliferation and retinal ganglion cell death, similar to Nf1 conditional knockout mice harboring a neomycin insertion (neo) as the germline Nf1 gene mutation. These differences in optic glioma phenotypes reflect both cell-autonomous and stromal effects of the germline Nf1 gene mutation. In this regard, primary astrocytes harboring the R681X germline Nf1 gene mutation exhibit increased basal astrocyte proliferation (BrdU incorporation) indistinguishable from neo(CKO) astrocytes, whereas astrocytes with the G848R mutation have lower levels of proliferation. Evidence for paracrine effects from the tumor microenvironment were revealed when R681X(CKO) mice were compared with conventional neo(CKO) mice. Relative to neo(CKO) mice, the optic gliomas from R681X(CKO) mice had more microglia infiltration and JNK(Thr183/Tyr185) activation, microglia-produced Ccl5, and glial AKT(Thr308) activation. Collectively, these studies establish that the germline Nf1 gene mutation is a major determinant of optic glioma development and growth through by both tumor cell-intrinsic and stromal effects.

  20. Optic Pathway Gliomas in Neurofibromatosis 1 (NF-1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-04-01

    Full Text Available Advances in the pathophysiology and clinical behavior of NF-1 associated optic pathway gliomas (OPG made over the past 10 years are examined, and evidence-based recommendations for diagnosis and management are proposed by researchers from Children's Memorial Hospital, Chicago; St Thomas's Hospital, London; Children's Hospital of Philadelphia; University of Pennsylvania School of Medicine, Philadelphia; and Washington University School of Medicine, St Louis, MO, The initial diagnostic and management guidelines proposed by a task force in 1997 are extended, and unanswered questions are addressed.

  1. Knowledge and Self-Esteem of Individuals with Neurofibromatosis Type 1 (NF1).

    Science.gov (United States)

    Rosnau, Kayla; Hashmi, S Shahrukh; Northrup, Hope; Slopis, John; Noblin, Sarah; Ashfaq, Myla

    2016-11-04

    Neurofibromatosis Type 1 (NF1) is a progressive genetic disorder characterized by physical findings such as café-au-lait macules, Lisch nodules, and neurofibromas in addition to other medical complications. Learning and social problems are more prevalent among individuals affected with NF1. It has been reported that people with NF1 have lower self-esteem (SE) when compared to the general population. Additionally, a study published over 20 years ago found that overall knowledge of NF1 was lacking in individuals affected with the condition. The goals of our study were to evaluate NF1 knowledge in adolescents and adults with the condition, as well as to determine if there is a link between patient knowledge and SE. Furthermore, we explored the impact of other factors, such as attendance at a NF1 support group and having a family history of NF1, on knowledge and SE. A survey comprised of knowledge-based questions and the Rosenberg Self-Esteem Scale was distributed to individuals with NF1 through the Texas NF Foundation. Overall, the 49 respondents (13 to 73 years of age) had a mean knowledge score of 77.9 % correct answers. Consistent with previous studies, the SE of our study population was lower when compared to general population norms. Although no correlation between knowledge and SE was observed, SE scores were on average higher if a person reported the following: having friends with NF1 (p = 0.009); attending a NF1 support group (p = 0.006); receiving care at a NF clinic (p = 0.049); or having received genetic counseling (p = 0.008). Further research is needed to better understand the relationship between these factors and SE in the NF1 population.

  2. The R1947X mutation of NF1 causing autosomal dominant neurofibromatosis type 1 in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    Qinbo Yang; Changzheng Huang; Xiaoying Yang; Yinfu Feng; Qing Wang; Mugen Liu

    2008-01-01

    Neurofibromatosis type 1 is a common autosomal dominant disorder with a high rate of penetrance. It is caused by the mutation of the tumor suppressor gene NF1, which encodes neurofibromin. The main function of neurofibromin is down-regulating the biological activity of the proto-oncoprotein Ras by acting as a Ras-specific GTPase activating protein. In this study, we identified a Chinese family affected with neurofibromatosis type 1. The known gene NF1 associated with NF1 was studied by linkage analysis and by direct sequencing of the entire coding region and exon-intron boundaries of the NF1 gene. The R1947X mutation of NF1 was identified, which was co-segregated with affected individuals in the Chinese family, but not present in unaffected family members. This is the first report, which states that the R1947X mutation of NF1 may be one of reasons for neurofibromatosis type 1 in Chinese population.

  3. Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients.

    Science.gov (United States)

    Nemethova, Martina; Bolcekova, Anna; Ilencikova, Denisa; Durovcikova, Darina; Hlinkova, Katarina; Hlavata, Anna; Kovacs, Laszlo; Kadasi, Ludevit; Zatkova, Andrea

    2013-09-01

    We performed a complex analysis of the neurofibromatosis type 1 (NF1) gene in Slovakia based on direct cDNA sequencing supplemented by multiple ligation dependent probe amplification (MLPA) analysis. All 108 patients had café-au-lait spots, 85% had axilary and/or inguinal freckling, 61% neurofibromas, 36% Lisch nodules of the iris and 31% optic pathway glioma, 5% suffered from typical skeletal disorders, and 51% of patients had family members with NF1. In 78 of the 86 (90.7%) index patients our analysis revealed the presence of NF1 mutations, 68 of which were small changes (87.2%), including 39 (50%) novel. Among the identified mutations the most prevalent were small deletions and insertions causing frameshift (42.3%), followed by nonsense (14.1%), missense (12.8%), and typical splicing (11.5%) mutations. Type 1 NF1 deletions and intragenic deletions/duplication were identified in five cases each (6.4%). Interestingly, in five other cases nontypical splicing variants were found, whose real effect on NF1 transcript would have remained undetected if using a DNA-based method alone, thus underlying the advantage of using the cDNA-based sequencing. We show that Slovak NF1 patients have a similar repertoire of NF1 germline mutations compared to other populations, with some prevalence of small deletions/insertions and a decreased proportion of nonsense mutations.

  4. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1.

    Science.gov (United States)

    Ko, Jung Min; Sohn, Young Bae; Jeong, Seon Yong; Kim, Hyon-Ju; Messiaen, Ludwine M

    2013-06-01

    Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations of the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of pseudogenes, and the great variety of mutations. Also, few probable genotype-phenotype correlations have been found in NF1. In this study 78 Korean patients from 60 families were screened for NF1 mutations. Mutation analysis of the entire coding region and flanking splice sites was carried out and included the use of a combination of reverse transcription polymerase chain reaction, multiplex ligation probe amplification, or fluorescence in situ hybridization. Mutation spectrum and genotype-phenotype relationship were assessed. Fifty-two distinct NF1 mutations were identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense), 11 missplicing mutations, seven small insertion or deletions, and four gross deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were recurrently identified. The mutations were evenly distributed across exon 1 through intron 47 of NF1, and no mutational hot spots were found. A genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. As technologies advance in molecular genetics, the mutation detection rate will increase. Considering that 30.8% of detected mutations were novel, exhaustive mutation analysis of NF1 may be an important tool in early diagnosis and genetic counseling.

  5. Fused teeth, macrodontia and increased caries are characteristic features of neurofibromatosis type 1 patients with NF1 gene microdeletion.

    Science.gov (United States)

    Kobayashi, Ryosuke; Matsune, Kensuke; Ohashi, Hirofumi

    2012-03-01

    Neurofibromatosis type 1 (NF1) is the most common genetic condition caused by NF1 gene alteration. A 1.5 Mb submicroscopic deletion encompassing the entire NF1 gene, is known to be responsible for approximately 5% of NF1 cases. Patients with NF1 deletion, compared to those with NF1 mutation tend to exhibit more severe phenotypes. To know the possible differences in oral/dental features between NF1 deletion and NF1 mutation patients, we examined four patients with NF1 deletion and three with NF1 mutation to compare their oral manifestations. Fused teeth in the mandibular anterior region were found only in the patients with deletion (2/4). Macrodontia was noted in all four patients with an NF1 deletion. Although macrodontia was also found in one patient with a mutation, it was relatively mild compared to the deletion patients. Dental caries were observed in both NF1 deletion (4/4) and mutation (2/3) patients. However, patients with NF1 deletions showed more apparently severe caries (average number of dental caries 12.8) than those with NF1 mutation (average number 5.5). Other features also noted in patients with both deletions and mutations were high-arched palate, hypodontia and malocclusion. Our study might suggest that fused teeth, macrodontia and increased dental caries are distinctive manifestations of NF1 deletion. Providing comprehensive dental care from early infancy would be very important to prevent dental caries especially in patients with NF1 deletion.

  6. [Neurofibromatosis von Recklinghausen type 1 (NF1) - clinical picture and molecular-genetics diagnostic].

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    Petrák, Bořivoj; Bendová, Šárka; Lisý, Jiří; Kraus, Josef; Zatrapa, Tomáš; Glombová, Marie; Zámečník, Josef

    2015-01-01

    Neurofibromatosis von Recklinghausen type 1 (NF1) is a multisystem, autosomal dominant hereditary neurocutaneous disease characterized by skin, central and peripheral nervous system , eyes , bone, endocrine, gastrointestinal and blood vessel wall involvement. It has an estimated frequency of 1 in 3000. Neurofibromatosis type 1 is caused by mutations in the large NF1 gene located on chromosome 17q11.2, encoding the cytoplasmic protein neurofibromin. It is expressed in multiple cell types but is highly expressed in Schwann cells, oligodendrocytes, neurons, astrocytes and leukocytes. Neurofibromin is known to act as a tumor suppressor via Ras-GTPase activation, which causes down-regulation of cellular signaling via the Ras/mitogen-activated protein kinase (MAPK) pathway. Failure of this function is associated with a tendency to form tumors which are histologically hamartomas as well as benign tumors. Tumors of the central nervous system include low-grade gliomas (pilocytic astrocytomas grade I), especially optic pathway gliomas. They are often clinically asymptomatic. Other intracranial tumors are in the brain stem and also elsewhere in the brain and spinal cord. Hydrocephalus may be a complication of NF1 gliomas or due to stenosis of the distal part of the aqueduct Silvii. Cutaneous and subcutaneous neurofibromas or plexiform neurofibromas are localized in the peripheral nervous system. Plexiform neurofibromas have a significant lifetime risk of malignancy. The clinical diagnosis of NF1 is defined by diagnostic criteria. The NF1 diagnosis is satisfied when at least two of the seven conditions are met. The method of direct DNA analysis of large NF1 gene (61 exons) is available. The results of studies of genotype - phenotype established few correlations. But predicting the disease by finding mutations is not currently possible. NF1 exhibits a wide range of variability of expression and complete penetrance, even within the same family. About half of cases are new

  7. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis.

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    Balgobind, Brian V; Van Vlierberghe, Pieter; van den Ouweland, Ans M W; Beverloo, H Berna; Terlouw-Kromosoeto, Joan N R; van Wering, Elisabeth R; Reinhardt, Dirk; Horstmann, Martin; Kaspers, Gertjan J L; Pieters, Rob; Zwaan, C Michel; Van den Heuvel-Eibrink, Marry M; Meijerink, Jules P P

    2008-04-15

    Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. Patients with NF1 have a higher risk to develop juvenile myelomonocytic leukemia (JMML) with a possible progression toward acute myeloid leukemia (AML). In an oligo array comparative genomic hybridization-based screening of 103 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL) and 71 patients with MLL-rearranged AML, a recurrent cryptic deletion, del(17)(q11.2), was identified in 3 patients with T-ALL and 2 patients with MLL-rearranged AML. This deletion has previously been described as a microdeletion of the NF1 region in patients with NF1. However, our patients lacked clinical NF1 symptoms. Mutation analysis in 4 of these del(17)(q11.2)-positive patients revealed that mutations in the remaining NF1 allele were present in 3 patients, confirming its role as a tumor-suppressor gene in cancer. In addition, NF1 inactivation was confirmed at the RNA expression level in 3 patients tested. Since the NF1 protein is a negative regulator of the RAS pathway (RAS-GTPase activating protein), homozygous NF1 inactivation represent a novel type I mutation in pediatric MLL-rearranged AML and T-ALL with a predicted frequency that is less than 10%. NF1 inactivation may provide an additional proliferative signal toward the development of leukemia.

  8. The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.

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    Pemov, A; Li, H; Patidar, R; Hansen, N F; Sindiri, S; Hartley, S W; Wei, J S; Elkahloun, A; Chandrasekharappa, S C; Boland, J F; Bass, S; Mullikin, J C; Khan, J; Widemann, B C; Wallace, M R; Stewart, D R

    2017-01-09

    Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDRNF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.Oncogene advance online publication, 9 January 2017; doi:10.1038/onc.2016.464.

  9. Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population.

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    Zhang, Jia; Tong, Hanxing; Fu, Xi'an; Zhang, Yong; Liu, Jiangbo; Cheng, Ruhong; Liang, Jianying; Peng, Jie; Sun, Zhonghui; Liu, Hong; Zhang, Furen; Lu, Weiqi; Li, Ming; Yao, Zhirong

    2015-06-09

    Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease that is primarily characterized by multiple café au-lait spots (CALs) and skin neurofibromas, which are attributed to defects in the tumor suppressor NF1. Because of the age-dependent presentation of NF1, it is often difficult to make an early clinical diagnosis. Moreover, identifying genetic alterations in NF1 patients represents a complex challenge. Currently, there are no effective detective methods, and no comprehensive NF1 mutation data are available for mainland China. We screened 109 Chinese patients from 100 families with NF1-like phenotypes (e.g., CALs, neurofibromas, etc.) using Sanger sequencing, multiplex ligation-dependent probe amplification and cDNA sequencing. NF1 mutations were identified in 97 individuals, among which 34 intragenic mutations have not previously been reported. Our exhaustive mutational analysis detected mutations in 89% (89/100) of the NF1-like probands and 93% (70/75) of subjects fulfilling the National Institutes of Health (NIH) criteria. Our findings indicate that individuals who exclusively present with multiple CALs exhibit a high possibility (76%) of having NF1 and show a significantly lower mutation rate (p = 0.042) compared with subjects who fulfill the NIH criteria, providing clinicians with the information that subjects only with multiple CALs harbor a considerable possibility (24%) of being attributed to other comparable diseases.

  10. Ras dependent paracrine secretion of osteopontin by Nf1+/- osteoblasts promote osteoclast activation in a neurofibromatosis type I murine model.

    Science.gov (United States)

    Li, Huijie; Liu, Yaling; Zhang, Qi; Jing, Yongmin; Chen, Shi; Song, Zhaohui; Yan, Jincheng; Li, Yan; Wu, Xiaohua; Zhang, Xianghong; Zhang, Yingze; Case, Jamie; Yu, Menggang; Ingram, David A; Yang, Feng-Chun

    2009-06-01

    Neurofibromatosis type 1 (NF1) is a pandemic genetic disorder characterized by malignant and nonmalignant manifestations, including skeletal abnormalities, such as osteoporosis, scoliosis, short stature, and pseudarthrosis. Recent studies in genetically inbred mice and from human patients with NF1 have identified multiple gains in osteoclast (OCL) functions both in vitro and in vivo. Given that osteoblasts secrete cytokines that promote OCL maturation/activation, we sought to identify whether haploinsufficiency of Nf1 (Nf1+/-) osteoblasts and their precursors secrete cytokines that have a central role in this process. Osteoblast conditioned media (OBCM) from Nf1+/- osteoblasts promoted OCL migration and bone resorption compared with WT OBCM. Osteopontin (OPN), a matrix protein found in mineralized tissues and pivotal in modulating OCL functions, was present in increased concentrations in Nf1+/- osteoblasts. Addition of OPN neutralizing antibody to Nf1+/- OBCM diminished the gain in bioactivity on OCL functions, including OCL migration and bone resorption. Our study identifies an important paracrine loop whereby elevated secretion of OPN by osteoblasts activate Nf1+/- OCLs that already have an intrinsic propensity for bone resorption leading to osteopenia and osteoporosis.

  11. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I.

    Science.gov (United States)

    Li, Kairong; Turner, Ashley N; Chen, Min; Brosius, Stephanie N; Schoeb, Trenton R; Messiaen, Ludwine M; Bedwell, David M; Zinn, Kurt R; Anastasaki, Corina; Gutmann, David H; Korf, Bruce R; Kesterson, Robert A

    2016-07-01

    Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681*) and a missense mutation (c.2542G>C; p.Gly848Arg). The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1(Arg681*) and missense NF1(Gly848Arg) mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1(Gly848Arg) mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1(Arg681*) mutation are not viable. Mice with one Nf1(Arg681*) allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf1(4F/Arg681*); DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  12. Screening in silico predicted remotely acting NF1 gene regulatory elements for mutations in patients with neurofibromatosis type 1.

    Science.gov (United States)

    Hamby, Stephen E; Reviriego, Pablo; Cooper, David N; Upadhyaya, Meena; Chuzhanova, Nadia

    2013-08-15

    Neurofibromatosis type 1 (NF1), a neuroectodermal disorder, is caused by germline mutations in the NF1 gene. NF1 affects approximately 1/3,000 individuals worldwide, with about 50% of cases representing de novo mutations. Although the NF1 gene was identified in 1990, the underlying gene mutations still remain undetected in a small but obdurate minority of NF1 patients. We postulated that in these patients, hitherto undetected pathogenic mutations might occur in regulatory elements far upstream of the NF1 gene. In an attempt to identify such remotely acting regulatory elements, we reasoned that some of them might reside within DNA sequences that (1) have the potential to interact at distance with the NF1 gene and (2) lie within a histone H3K27ac-enriched region, a characteristic of active enhancers. Combining Hi-C data, obtained by means of the chromosome conformation capture technique, with data on the location and level of histone H3K27ac enrichment upstream of the NF1 gene, we predicted in silico the presence of two remotely acting regulatory regions, located, respectively, approximately 600 kb and approximately 42 kb upstream of the NF1 gene. These regions were then sequenced in 47 NF1 patients in whom no mutations had been found in either the NF1 or SPRED1 gene regions. Five patients were found to harbour DNA sequence variants in the distal H3K27ac-enriched region. Although these variants are of uncertain pathological significance and still remain to be functionally characterized, this approach promises to be of general utility for the detection of mutations underlying other inherited disorders that may be caused by mutations in remotely acting regulatory elements.

  13. Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I

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    Kairong Li

    2016-07-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models available for assessing patient-specific mutations. In order to test therapeutic approaches that might restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C>T; p.Arg681* and a missense mutation (c.2542G>C; p.Gly848Arg. The latter is associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects on neurofibromin expression in the mouse and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681* allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F/Arg681*; DhhCre display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for preclinical testing of novel nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in individuals with NF1.

  14. Conflict processing in juvenile patients with neurofibromatosis type 1 (NF1) and healthy controls - Two pathways to success.

    Science.gov (United States)

    Bluschke, Annet; von der Hagen, Maja; Papenhagen, Katharina; Roessner, Veit; Beste, Christian

    2017-01-01

    Neurofibromatosis Type 1 (NF1) is a monogenetic autosomal-dominant disorder with a broad spectrum of clinical symptoms and is commonly associated with cognitive deficits. Patients with NF1 frequently exhibit cognitive impairments like attention problems, working memory deficits and dysfunctional inhibitory control. The latter is also relevant for the resolution of cognitive conflicts. However, it is unclear how conflict monitoring processes are modulated in NF1. To examine this question in more detail, we used a system neurophysiological approach combining high-density ERP recordings with source localisation analyses in juvenile patients with NF1 and controls during a flanker task. Behaviourally, patients with NF1 perform significantly slower than controls. Specifically on trials with incompatible flanker-target pairings, however, the patients with NF1 made significantly fewer errors than healthy controls. Yet, importantly, this overall successful conflict resolution was reached via two different routes in the two groups. The healthy controls seem to arrive at a successful conflict monitoring performance through a developing conflict recognition via the N2 accompanied by a selectively enhanced N450 activation in the case of perceived flanker-target conflicts. The presumed dopamine deficiency in the patients with NF1 seems to result in a reduced ability to process conflicts via the N2. However, NF1 patients show an increased N450 irrespective of cognitive conflict. Activation differences in the orbitofrontal cortex (BA11) and anterior cingulate cortex (BA24) underlie these modulations. Taken together, juvenile patients with NF1 and juvenile healthy controls seem to accomplish conflict monitoring via two different cognitive neurophysiological pathways.

  15. [Molecular diagnosis as a strategy for differential diagnosis and at early ages of neurofibromatosis type 1 (NF1)].

    Science.gov (United States)

    Gómez, Martha; Batista, Oriana

    2015-10-01

    Neurofibromatosis type 1 (NF1), is a haploinsufficient and multisystemic disease, caused by inherited or sporadic mutations in the NF1 gene. Its incidence is one in 2,500 to 3,000 individuals, it has an autosomal dominant pattern of inheritance, high clinical variability, complete penetrance and age-dependent complications. Neurofibromin is the product of the NF1 gene and is believed to act as a tumor suppressor since the loss of its function has been associated with benign and malignant tumors in neural crest-derived tissues. Only two correlations between clinical phenotype and mutant alleles in the NF1 gene have been observed. The established criteria for disease diagnosis are very efficient in adults and children older than 3 years of age, but not for children under this age. Mutational analysis is therefore recommended to confirm the disease in young children with a negative family history. A pathogenic mutation in the NF1 should be added to the list of diagnostic criteria. Mutational analysis is also recommended for differential diagnosis and for prenatal or pre-implantation genetic diagnosis, taking into consideration the family history and the type of method to be applied. Molecular studies of this disease using different complimentary molecular techniques and bioinformatics tools have characterized NF1 gene mutations at both the DNA and mRNA levels, increasing the mutational spectrum. Consequently, about 1,289 defects have been reported to date, mainly nonsense/missense mutations, deletions and splice site defects.

  16. Mutational analysis of the GAP-related domain of the neurofibromatosis type 1 gene in Brazilian NF1 patients

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    Alessandra B. Trovó

    2004-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common autosomal dominant disorder caused by mutations in the NF1 gene. In the present study, a total of 55 unrelated NF1 patients were screened for mutations in the GAP-related domain/GRD (exons 20-27a by single-strand conformation polymorphism (SSCP. Four different mutations were identified and, taken together, they comprise one nonsense substitution (Q1189X, one deletion (3525-3526delAA, one missense substitution (E1356G and one mutation in the splice acceptor site (c.4111-1G>A. One novel polymorphism (c.4514+11C>G and other three putative polymorphisms were also found (c.3315-27G>A, V1146I and V1317A. Genotype-phenotype correlations were investigated, but no particular association was detected.

  17. Computed tomography (CT) findings in 88 neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic findings

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    Ueda, Ken, E-mail: k-ueda@radiol.med.osaka-u.ac.jp [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Honda, Osamu [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Satoh, Yukihisa [Department of Diagnostic Radiology, Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan); Kawai, Misa; Gyobu, Tomoko; Kanazawa, Toru; Hidaka, Shojiro; Yanagawa, Masahiro [Department of Radiology, Osaka University Graduate School of Medicine (Japan); Sumikawa, Hiromitsu [Department of Diagnostic Radiology, Osaka Rosai Hospital (Japan); Tomiyama, Noriyuki [Department of Radiology, Osaka University Graduate School of Medicine (Japan)

    2015-06-15

    Highlights: • Various thoracic CT findings, including cysts, mediastinal masses, etc. were found. • Cysts show upper and peripheral dominant distribution. • The number, size, and distribution of the pulmonary cysts in NF-1 revealed significant correlation. • It is suspected that thoracic CT findings in NF-1 occur independently. - Abstract: Purpose: To evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. Materials and methods: Chest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. Results: Of the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. Conclusion: Various CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and

  18. Neurofibromatosis tipo 1 (NF1 revisión y presentación de un caso clínico con manifestaciones bucofaciales Neurofibromatosis type 1 (NF1 review and report of a case with buccofacial manifestations

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    JJ Orozco Ariza

    2005-10-01

    Full Text Available La neurofibromatosis es una enfermedad hereditaria de transmisión autosómica dominante que compromete el desarrollo de las células de la cresta neural. Las manifestaciones bucofaciales de la neurofibromatosis tipo 1 (NF1 son muy escasas, presentando una prevalencia de 1:16.000. El caso que se presenta es de un paciente varón de 10 años de edad, de raza negra, que acudió al Servicio de Cirugía Oral y Maxilofacial del Hospital Universitario de Cartagena de Indias (Colombia por presentar un nódulo en el suelo de la boca y una ligera asimetría facial provocada por una hipertrofia fibrosa que comprometía el maxilar superior y el cuerpo mandibular izquierdo. En el examen físico se encontraron, a nivel cutáneo, numerosas manchas café con leche dispersas por todo el cuerpo, mientras que la exploración oftalmológica reveló múltiples nódulos de Lisch (hamartomas del iris. Las imágenes radiográficas mostraron una compresión extraósea y la tomografía computadorizada (TC descartó la presencia de glioma de los nervios ópticos. Como antecedentes familiares, el padre, una hermana y una tía del paciente presentaban una NF1 confirmada clínicamente. De acuerdo con la determinación de los criterios diagnósticos de la NF1 establecidos en 1987 por el "National institut of health concensus development conference on neurofibromatosis", esos tres hallazgos permitieron hacer un diagnóstico de NF1 y orientar la impresión clínica de las lesiones bucofaciales hacia neurofibromas, lo que fue confirmado histológicamente. El manejo de los pacientes con NF1 es difícil, como también lo es el tratamiento de las complicaciones que pueden producir las lesiones tales como deformidades (con el consiguiente problema psicológico, gliomas de los nervios ópticos (ceguera o un alto riesgo de malignización. La ayuda del consejo genético, el aislamiento del gen implicado y los últimos avances en el campo de la genética, son muy esperanzadoras en

  19. Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer.

    Science.gov (United States)

    Campos, Berta; Balmaña, Judith; Gardenyes, Josep; Valenzuela, Irene; Abad, Oscar; Fàbregas, Pere; Volpini, Víctor; Díez, Orland

    2013-06-01

    Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are café-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed.

  20. Mutation analysis of the NF1 gene in two patients with neurofibromatosis type I%I型神经纤维瘤病NF1基因突变检测

    Institute of Scientific and Technical Information of China (English)

    王晓光; 马玉萍; 郝运宏; 金倩; 周海燕; 张琳; 李桂英; 林志淼

    2014-01-01

    目的:检测I型神经纤维瘤病患者的NF1基因突变。方法:提取I型神经纤维瘤病1家系、1例散发患者及200名正常对照外周血DNA,PCR扩增NF1基因全部外显子及侧翼序列并进行Sanger测序。结果:在家系的先证者及其母亲外周血DNA中检测到NF1基因c.3975-2 A>T突变,其他家系成员未发现突变位点;在散发病例中检测到c.3619delA突变,为国际上首次报道。结论: I型神经纤维瘤病具有遗传基因异质性。%Objective:To determine NF1 gene mutations in one family and one sporadic case with neurofi-bromatosis type I. Methods:All exons and flanking sequences of the NF1 gene of patients and controls were amplified by PCR and DNA sequencing was followed. Results:A heterozygous splicing mutation ( c.3975-2A>T) of NF1 gene in the proband and the mother of the proband of the family was identified. A heterozygous frameshift mutation ( c.3619delA) was identified in the sporadic patients with neurofibromatosis type I,which was the first report up to now. Conclusion:There exists a genetic heterogeneity in neurofibromatosis type I.

  1. Radiation Therapy in Management of Sporadic and Neurofibromatosis Type 1 (NF1 Associated Malignant Peripheral Nerve Sheath Tumors (MPNST

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    Jenna eKahn

    2014-11-01

    Full Text Available Introduction: Malignant peripheral nerve sheath tumors (MPNST are highly aggressive soft tissue sarcomas in which complete surgical resection is the mainstay of therapy. However, the recurrence rate is high and few options remain for refractory or metastatic MPNST. This study examines the outcomes of adjuvant radiation therapy in MPNST in patients with and without neurofibromatosis-1 (NF1 and reviews the literature on use of radiation for MPNST. Methods: A retrospective review of 33 MPNST patients between 1990 and 2012 evaluated at the NIH. All diagnoses were pathologically confirmed at the NCI. Clinical presentation, treatment, and survival were analyzed. Results: Thirty-three patients were included, 18 NF1-associated, 15 sporadic tumors. Tumor location included extremity (58%, trunk (36%, and head/neck (6%. Histologic grade showed 25 high grade tumors compared to 7 low grade tumors. Twenty patients were treated with radiation therapy, (median total dose of 58.5 Gy with 1.8 Gy/fraction. A median survival of all patients was 46.5 months and 43.7% overall 5 year survival. Prognostic factors include extent of resection, tumor location, and histology grade. Radiation was not found to be a prognostic factor for overall survival. Conclusions: This study is consistent with previous studies regarding the role of radiation in the management of MPNST. Prospective evaluation of adjuvant radiation will allow to more fully define the role of radiation in MPNST.

  2. NF1 frameshift mutation (c.6520_6523delGAGA) association with nervous system tumors and bone abnormalities in a Chinese patient with neurofibromatosis type 1.

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    Su, S Y; Zhou, X; Pang, X M; Chen, C Y; Li, S H; Liu, J L

    2016-04-07

    Neurofibromatosis type 1, also known as NF1 or von Recklinghausen's disease, is a common neurocutaneous syndrome that presents with multiple café-au-lait patches, skinfold freckling, dermatofibromas, neurofibromas, and Lisch nodules. The mutations of the gene NF1, encoding the protein neurofibromin, have been identified as the cause of this disease. Here, we report a clinical and molecular study of a Chinese patient with multiple café-au-lait skin freckles, dermatofibroma, central and peripheral nervous system tumors, and bone abnormalities attributed to NF1. The patient showed >6 café-au-lait spots on the body and multiple dermatofibromas. A brain glioma and multiple nerve sheath tumors inside and outside the vertebral canal were identified by magnetic resonance imaging, which also showed multiple intercostal nerve schwannomas and hydrocephalies above the cerebellar tentorium. Talipes equinus was also apparent. A mutation analysis of the NF1 gene revealed a novel frameshift mutation in exon 43, consisting of a heterozygous deletion of four nucleotides (GAGA) between positions 6520 and 6523. No NF1 mutations were detected in the patient's parents or younger brother. These results extend the list of known mutations in this gene. The absence of the NF1 mutation in the healthy family members suggests that it is responsible for the NF1 phenotype. To our knowledge, this frameshift mutation represents a novel NF1 case, and may be associated with nervous system tumors and bone abnormalities.

  3. Neurofibromatosis

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    Gerber PA

    2009-03-01

    Full Text Available Abstract Neurofibromatosis (NF is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1, also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2, previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi-or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.

  4. A novel NF1 frame-shift mutation (c.702_703delGT) in a Chinese family with neurofibromatosis type 1.

    Science.gov (United States)

    Cai, S P; Fan, N; Chen, J; Xia, Z L; Wang, Y; Zhou, X M; Yin, Y; Wen, T L; Xia, Q J; Liu, X Y; Wang, H Y

    2014-07-24

    This study aimed to characterize the clinical features of a Chinese pedigree with neurofibromatosis type 1 (NF1) and to identify mutations in the NF1 gene. In this three-generation family containing 8 members, 5 had been diagnosed with NF1 and the others were asymptomatic. All members of the family underwent complete medical examinations. Molecular genetic analyses were performed on all subjects included in the study. All exons of NF1 were amplified by polymerase chain reaction, sequenced, and compared with a reference database. Possible changes in function of the protein induced by amino acid variants were predicted by bioinformatic analysis. In this family, the 5 patients presented different clinical phenotypes, but all manifested typical café-au-lait macules. One novel frame-shift mutation, c.702_703delGT, in exon 7 of NF1 was identified in all affected family members, but not in the unaffected family members or in 102 normal controls. This mutation generates a premature stop codon at amino acid position 720. Additionally, a synonymous mutation c.702 G>A was found in 3 family members, including 2 affected and 1 normal individuals. In conclusion, our study suggests that a novel c.702_703delGT frame-shift mutation in NF1 is likely to be responsible for the pathogenesis of NF1 in this family. To the best of our knowledge, it is the first time that a c.702_703delGT mutation has been identified in a family with neurofibromatosis type 1.

  5. Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes.

    Science.gov (United States)

    Ercolino, Tonino; Lai, Roberta; Giachè, Valentino; Melchionda, Salvatore; Carella, Massimo; Delitala, Alessandro; Mannelli, Massimo; Fanciulli, Giuseppe

    2014-02-25

    Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease with an estimated incidence of 1 in 3000/3500 live births. NF1 is caused by a mutation in a gene which encodes a protein known as neurofibromin. In up to 5% of cases, NF1 is associated with pheochromocytomas. RET proto-oncogene encodes a member of the receptor tyrosine kinase family involved in the normal development or the neoplastic growth of neural crest cell lineages. Germ-line RET mutations account for cases of Multiple Endocrine Neoplasia type 2 (MEN2), an autosomal dominant genetic syndrome where medullary thyroid carcinoma (MTC) is the major and more clinically severe feature, with nearly complete penetrance. C-cell hyperplasia (CCH) is described in MEN2 patients, and it has been implicated as the precursor of in situ MTC. Patients with RET mutations develop pheochromocytomas in 50% of cases. Rarely, patients with NF1 have been found to present, in addition to the NF1 clinical picture, other lesions, such as parathyroid hyperplasia/adenoma and/or medullary thyroid carcinoma. In spite of the presence of these MEN2 lesions, in none of these patients mutations of gene RET have been found so far. In this report, we describe the first case of a patient affected by a germ-line mutation in both NF1 and RET genes.

  6. Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in neurofibromatosis type I (NF1) disease model cells.

    Science.gov (United States)

    Hirayama, Mio; Kobayashi, Daiki; Mizuguchi, Souhei; Morikawa, Takashi; Nagayama, Megumi; Midorikawa, Uichi; Wilson, Masayo M; Nambu, Akiko N; Yoshizawa, Akiyasu C; Kawano, Shin; Araki, Norie

    2013-05-01

    Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up- or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural

  7. NF1 deficiency causes Bcl-xL upregulation in Schwann cells derived from neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

    Science.gov (United States)

    Park, Ho-Jin; Lee, Su-Jin; Sohn, Young Bae; Jin, Hyun-Seok; Han, Jae-Ho; Kim, Young-Bae; Yim, Hyunee; Jeong, Seon-Yong

    2013-02-01

    Since the bi-allelic inactivation of both neurofibromin 1 (NF1) gene alleles (NF1(-/-)) in Schwann cells (SCs) is common in both benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1 (NF1), other genetic alterations in SCs may be required for tumor progression of PNs to MPNSTs. We found that the anti-apoptotic Bcl-xL protein is upregulated in MPNST tissues compared to PN tissues from patients with NF1 by immunohistological staining. In addition, we investigated whether Bcl-xL is upregulated in SCs derived from MPNSTs and found a significantly higher Bcl-xL expression level in sNF96.2 MPNST-derived SCs compared to normal human SCs (HSCs). We also discovered that the increased Bcl-xL expression caused an increase in drug resistance to doxorubicin in MPNST-derived SCs. Manipulation of NF1 gene expression levels by treatment with small interfering RNA (siRNA) and overexpression of the neurofibromin GAP-related domain (NF1-GRD) demonstrated that upregulated Bcl-xL expression in MPNST-derived SCs was caused by NF1 deficiency. Treatment with the Erk1/2 inhibitor, PD98059, resulted in a slight increase in Bcl-xL levels in neurofibromin-depleted normal HSCs, indicating that Bcl-xL upregulation in MPNST-derived SCs is mediated by activated Erk1/2, which is a Ras downstream protein regulated by neurofibromin. As the reduction of Bcl-xL expression restored sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, we examined the effect of the small molecule Bcl-xL inhibitor ABT-737 on sNF96.2 cells. A very low dose of ABT-737 combined with doxorubicin synergistically enhanced sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, suggesting that ABT-737 and doxorubicin may be a good combination to effectively treat NF1-associated MPNSTs with minimal side-effects. Collectively, our results suggest that upregulation of Bcl-xL in MPNST-derived SCs may be caused by the NF1 deficiency

  8. Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT).

    Science.gov (United States)

    Morris, Stephanie M; Acosta, Maria T; Garg, Shruti; Green, Jonathan; Huson, Susan; Legius, Eric; North, Kathryn N; Payne, Jonathan M; Plasschaert, Ellen; Frazier, Thomas W; Weiss, Lauren A; Zhang, Yi; Gutmann, David H; Constantino, John N

    2016-12-01

    Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of

  9. Acceptance and commitment therapy in youth with neurofibromatosis type 1 (NF1) and chronic pain and their parents: A pilot study of feasibility and preliminary efficacy.

    Science.gov (United States)

    Martin, Staci; Wolters, Pamela L; Toledo-Tamula, Mary Anne; Schmitt, Shawn Nelson; Baldwin, Andrea; Starosta, Amy; Gillespie, Andrea; Widemann, Brigitte

    2016-06-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder affecting about 1 in 3,500 individuals. Chronic pain is commonly reported among individuals with NF1 and plexiform neurofibroma tumors (PNs). Acceptance and Commitment Therapy (ACT), an empirically supported method for addressing chronic pain, helps individuals re-focus on valued relationships and activities. This pilot study investigated the feasibility and preliminary efficacy of a brief ACT workshop in the NF1 population. Eligible participants included adolescents and young adults (AYA; 12-21 years) with NF1 and chronic pain that interfered with daily functioning and their parents. Patients and parents completed baseline measures of pain interference, pain intensity, functional disability, pain acceptance, depression, and anxiety. Then, AYA and parents participated separately in a 2-day small-group ACT workshop. A telephone booster session occurred 1 month post-intervention. Three-month post-treatment measures were completed by mail. Ten adolescents (4 males; M age = 16.9 years) and seven parents provided baseline and 3-month data. Mean satisfaction with the study was moderate to high (3.9 for patients and 4.6 for parents on a 1-5 scales). Patients and parents reported significant declines in patients' pain interference at 3 months post-treatment. Patient-reported pain intensity significantly declined from baseline to 3 months. Parents reported marginally greater acceptance of their child's pain. No changes emerged in functional ability or mood. Preliminary findings suggest that a brief ACT group intervention is feasible and may help AYA with NF1 and PNs cope with their chronic pain, although larger randomized studies are needed to confirm treatment efficacy. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Pilot Study of Gleevec/Imatinib Mesylate (STI 571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas

    Science.gov (United States)

    2016-03-01

    representative cases for the NF1 tumors pre and post Gleevec treatment. The left of each of these images is the B0 DWI MRI to show anatomy and the right is the...Pre Treatment ( Anatomy ) P A I S Pre Treatment (Tumor) P A I S Post Treatment ( Anatomy ) P A I S Post Treatment (Tumor) R L P A R...assays Name: Cindy Elkins, RN Role: Research Nurse Person-months-worked per year: 2.4 Contribution to Project: Enrollment of Patients 21 Name

  11. One novel mutation and copy number variation of NF1 gene in Chinese patients with type 1 neurofibromatosis%NF1基因新突变及我国首例NF1基因拷贝数目变异报道

    Institute of Scientific and Technical Information of China (English)

    邓佳; 邓伟平; 钟诚; 胡彬; 王一鸣

    2013-01-01

    AIM: To investigate the mutations and the copy number variation of neurofibromatosis l(NFl') gene in 2 sporadic patients with type 1 neurofibromatosis in China. METHODS: All coding exons and exon-intron boundaries of NF1 were amplified by PCR. The PCR products were sequenced. The DNA samples from 50 normal subjects were also sequenced for control. Multiplex ligation-dependent probe amplification (MLPA) was also employed to detect the copy number variation of NF1 gene in these patients. Long range PCR was used for the identification of the breakpoint in the large deletion of the gene. RESULTS: The novel mutation, c. 6345_6346 ins G (p. Leu2116Alafs * 4) , was detected in patient S736. This mutation was absent in her parents and the controls, indicating a de novo mutation. It caused open reading frame shifting, introducing a premature stop codon and resulting in the truncation of the 721 amino acids at the C terminus of the wild-type protein. This truncation cut off part of the armadillo (ARM)-type fold domain in the wild-type protein. A 1.3 ~ 1. 9 Mb deletion of the gene was also detected in the other patient S743. The deletion spanned the whole NF1 gene and part of the flanking regions in both ends, but the breaking point was still unknown. CONCLUSION: We have identified a novel mutation of NF1, c.6345_6346 ins G (p. Leu2116Alafs *4) . We also first report the copy number variation of NF1 gene in Chinese patients. The investigation will be helpful for the molecular diagnosis and understanding the pathogenesis of the disease.%目的:对2例散发性1型神经纤维瘤患者进行致病基因NF1编码序列的突变筛查以及拷贝数变异(copy number variation,CNV)研究,寻找致病性突变.方法:PCR扩增NF1基因的编码区及外显子-内含子交界区,对产物进行直接测序.在50例正常对照中进行新发现突变位点的测序分析,以排除多态性.用多重连接探针扩增技术(MLPA)对患者进行NF1基因CNV的检测,并对证实有NF

  12. Neurofibromatosis

    Science.gov (United States)

    Neurofibromatosis is a genetic disorder of the nervous system. It mainly affects how nerve cells form and ... tumors to grow on nerves. You can get neurofibromatosis from your parents, or it can happen because ...

  13. A novel mutation in NF1 is associated with diverse intra-familial phenotypic variation and astrocytoma in a Chinese family.

    Science.gov (United States)

    Banerjee, Santasree; Dai, Yi; Liang, Shengran; Chen, Huishuang; Wang, Yanyan; Tang, Lihui; Wu, Jing; Huang, Hui

    2016-09-01

    Neurofibromatosis type 1 (NF1) is a dysregulated neurocutaneous disorder, characterized by neurofibromas and café-au-lait spots. NF1 is caused by mutations in the NF1 gene, encoding neurofibromin. Here, we present a clinical molecular study of a three-generation Chinese family with NF1. The proband was a male patient who showed café-au-lait spots and multiple subcutaneous neurofibromas over the whole body, but his siblings only had regional lesions. The man's daughter presented with severe headache and vomiting. Neurological examination revealed an intracranial space occupying lesion. Surgery was undertaken and the histopathological examination showed a grade I-II astrocytoma. Next-Generation sequencing (Illumina HiSeq2500 Analyzers; Illumina, San Diego, CA, USA) and Sanger sequencing (ABI PRISM 3730 automated sequencer; Applied Biosystems, Foster City, CA, USA) identified the c.227delA mutation in the NF1 gene in the man. The mutation is co-segregated with the disease phenotypes among the affected members of this family and was absent in 100 healthy controls. This novel mutation results in a frameshift (p.Asn78IlefsX7) as well as truncation of neurofibromin by formation of a premature stop codon. Our results not only extended the mutational and phenotypic spectra of the gene and the disease, but also highlight the importance of the other genetic or environmental factors in the development and severity of the disease.

  14. Recurrent multilocular mandibular giant cell granuloma in neurofibromatosis type 1: Evidence for second hit mutation of NF1 gene in the jaw lesion and treatment with curettage and bone substitute materials.

    Science.gov (United States)

    Friedrich, Reinhard E; Grob, Tobias J; Hollants, Silke; Zustin, Jozef; Spaepen, Marijke; Mautner, Victor F; Luebke, Andreas M; Hagel, Christian; Legius, Eric; Brems, Hilde

    2016-08-01

    Giant cell granuloma (GCG) of the jaw is a rare, well-known feature of neurofibromatosis type 1 (NF1), an inborn multisystem disorder. Recently, the development of GCG in NF1 was attributed to second hit mutations in the NF1 gene. The treatment of GCG is pragmatic with a preference for local curettage of lytic osseous areas. This report describes the surgical therapy of an NF1-affected female with multilocular mandibular GCG and hypodontia who additionally suffered from a brain tumour and Hashimoto's thyroiditis. Although local recurrence of GCG was noted, augmentation of the curetted cavities with a bone substitute in successive interventions successfully restored the extensive periradicular local defects and stabilised the teeth. A meticulous in vitro study of the GCG specimen revealed a second hit mutation in the NF1 gene in the GCG spindle-cells. This study contributes to the increasing knowledge of the molecular basis for GCG in the jaw of NF1 patients, indicating that it is a neoplasm.

  15. Elevated Risk for MPNST in NF1 Microdeletion Patients

    OpenAIRE

    De Raedt, T.; Brems, H.; Wolkenstein, P.; Vidaud, D; Pilotti, S; Perrone, F.; Mautner, V; Frahm, S.; Sciot, R; Legius, E

    2003-01-01

    An NF1 microdeletion is the single most commonly reported mutation in individuals with neurofibromatosis type 1 (NF1). Individuals with an NF1 microdeletion have, as a group, more neurofibromas at a younger age than the group of all individuals with NF1. We report that NF1 microdeletion individuals additionally have a substantially higher lifetime risk for the development of malignant peripheral nerve sheath tumors than individuals with NF1 who do not have an NF1 microdeletion. This should be...

  16. Phenotypic characterization of transgenic mice harboring Nf1+/- or Nf1-/- osteoclasts in otherwise Nf1+/+ background.

    Science.gov (United States)

    Alanne, Maria H; Siljamäki, Elina; Peltonen, Sirkku; Väänänen, Kalervo; Windle, Jolene J; Parada, Luis F; Määttä, Jorma A; Peltonen, Juha

    2012-06-01

    Skeletal abnormalities in neurofibromatosis type 1 syndrome (NF1) are observed in ∼50% of patients. Here, we describe the phenotype of Nf1(Ocl) mouse model with Nf1-deficient osteoclasts. Nf1Ocl mice with Nf1+/- or Nf1-/- osteoclasts in otherwise Nf1+/+ background were successfully generated by mating parental Nf1flox/flox and TRAP-Cre mice. Contrary to our original hypothesis, osteoporotic or fragile bone phenotype was not observed. The µCT analysis revealed that tibial bone marrow cavity, trabecular tissue volume, and the perimeter of cortical bone were smaller in Nf1 Ocl-/- mice compared to Nf1 Ocl+/+ control mice. Nf1 Ocl-/- mice also a displayed narrowed growth plate in the proximal tibia. In vitro analysis showed increased bone resorption capacity and cytoskeletal changes including irregular cell shape and abnormal actin ring formation in Nf1-/- osteoclasts. Surprisingly, the size of spleen in Nf1 Ocl-/- mice was two times larger than in controls and histomorphometric analysis showed splenic megakaryocytosis. In summary, Nf1Ocl mouse model presented with a mild but specific bone phenotype. This study shows that NF1-deficiency in osteoclasts may have a role in the development of NF1-related skeletal abnormalities, but Nf1-deficiency in osteoclasts in Nf1+/+ background is not sufficient to induce skeletal abnormalities analogous to those observed in patients with NF1.

  17. 两例I型神经纤维瘤病NF1基因突变检测%Identification of mutation of NF1 gene in two Chinese patients with neurofibromatosis type 1

    Institute of Scientific and Technical Information of China (English)

    陈滨; 孙良丹; 周伏圣; 方巧云; 杜文辉; 权晟; 杨森; 张学军

    2008-01-01

    目的: 检测2例I型神经纤维瘤病(NF1)患者NF1基因的突变情况.方法: 采用聚合酶链反应(PCR)和DNA测序法对2例NF1患者及100例无亲缘关系的正常人进行NF1基因突变检测.结果: 在2例NF1患者中检测到两个突变:无义突变c.1009G>T和移码突变c.3443-3444delCA,在患者家属中正常人及100例无亲缘关系的正常对照中均未检测到上述突变,该2个突变以前在国内外均未见报道.结论: 2例NF1患者中NF1基因的新发现的无义突变c.1009G>T和移码突变c.3443-3444delCA,不是罕见的单核苷酸多态,可能是致病突变,通过影响NF1基因的功能而引发患者发病.

  18. Identification of a mosaic mutation of NF1 gene in a sporadic case of neurofibromatosis type 1%一例散发1型神经纤维瘤病患者的NF1基因嵌合突变分析

    Institute of Scientific and Technical Information of China (English)

    周春燕; 李军; 郭小艳; 廖娟; 王志红; 兰风华

    2012-01-01

    目的 对1例散发1型神经纤维瘤病患者的NF1基因进行嵌合突变分析.方法 提取先证者外周血基因组RNA,PCR扩增NF1基因编码区序列并进行序列测定;找到突变后,基因组DNA途径证实突变,并对先证者儿子的NF1基因相应外显子也进行序列分析;针对NF1基因第51外显子已发现的突变,取先证者全血淋巴细胞、口腔上皮细胞和尿路上皮细胞基因组DNA进行PCR扩增,PCR产物T克隆及测序.结果 先证者的临床表现符合1型神经纤维瘤病.先证者外周血RNA途径检测出无义突变c.7911C>T(p.Q2510X);基因组DNA途径证实患者外周血淋巴细胞、口腔上皮细胞和尿路上皮细胞中均有该突变,尿路上皮细胞中该突变测序信号较弱;在PCR产物的T克隆-测序中,来自先证者的血液、口腔上皮、尿液上皮细胞无义突变c.7911C>T(p.Q2510X)突变体的重组菌分别占总数的42%、36%、12%.其儿子、正常对照不存在上述突变.结论 先证者在胚胎早期发生了NF1基因突变,使其体内部分细胞带有NF1基因突变,导致形成全身嵌合的1型神经纤维瘤病.%Objective To detect NF1 gene mutation in a patient with neurofibromatosis type 1.Methods Five fragments encompassing the entire coding sequence of the NF1 gene were amplified with reverse transcription PCR.PCR products were directly sequenced.Suspected mutations were verified by sequencing of DNA amplified by PCR using genomic DNA as template.Corresponding exon of family members was also sequenced.Furthermore,the PCR products were inserted into a pGEM-T cloning vector to quantify cells carrying the mutation in different samples derived from the three embryonic layers.Results The proband's clinical manifestation was consistent with neurofibromatosis type 1.Sequence analysis has identified a novel heterozygous mutation c.7911C>T (p.Q2510X) in exon 51 of the NF1 gene in the proband.The same mutation was also detected in

  19. 二例散发型Ⅰ型神经纤维瘤病患儿的NF1基因突变分析%Molecular analysis of two pediatric cases with sporadic neurofibromatosis type 1

    Institute of Scientific and Technical Information of China (English)

    张佳; 李明; 姚志荣

    2016-01-01

    Objective To report on two children manifesting multiple café-au-lait spots suspected as neurofibromatosis type 1,and perform NF1 gene mutation analysis.Methods Blood samples were collected from the 2 children,their unaffected parents and 100 normal controls.The entire coding region of the NF1 gene was amplified by PCR and subjected to direct sequencing.Results In patient 1,a novel frameshift mutation c.1948delT (p.Leu650TyrfsX38) was identified in exon 12 of the NF1 gene.And in patient 2,a previously reported nonsense mutation c.541C>T (p.Gln181X) was revealed in exon 4b.The same mutations were not detected in their unaffected parents or 100 normal controls.Conclusion The two patients were diagnosed with neurofibromatosis type 1 by molecular genetic testing.The pathogenic mutations were c.1948delT and c.541C>T,respectively.%目的 对2例无家族史、主要表现为多发咖啡斑、怀疑为Ⅰ型神经纤维瘤病的患儿进行NF1基因突变检测.方法 抽取2例患儿及其表型正常父母的血液样本,同时采集正常对照血样100份,应用PCR技术对NF1基因全部编码区进行扩增,并进行直接测序.结果 直接测序结果显示例1 NF1基因第12外显子存在1个新的c.1948delT(p.Leu650TyrfsX38)移码突变;例2 NF1基因第4b外显子存在1个已报道的c.541C>T(p.Gln181X)无义突变.二者的父母检测均为阴性,在100份正常对照也未发现上述突变.结论 应用基因突变检测确诊2例散发的Ⅰ型神经纤维瘤病例.NF1基因突变分别为c.1948delT和c.541C>T.

  20. 一例神经纤维瘤病Ⅰ型患者NF1基因新的插入缺失型突变%A novel indel NF1 mutation identified in a patient with neurofibromatosis type 1

    Institute of Scientific and Technical Information of China (English)

    朱铁山; 黄尚志; 伍建; 汪春丹; 杨涛

    2015-01-01

    Objective To identify the genetic etiology in a Chinese patient with neurofibromatosis type 1 (NF-1).Methods All coding exons and the flanking sequences of neurofibromin 1 (NF1)gene from the patient were captured,individually barcoded and subjected to HiSeq2000 high-throughput sequencing.Suspected mutation was validated in the nuclear family members with Sanger sequencing.Results A novel indel mutation,c.789_790delAGinsT,was identified in the exon 8 of the NF1 gene in the patient but not in her asymptomatic parents.The mutation was predicted to have caused shifting of the reading frame and a premature downstream stop codon (p.K263Nfs * 18).Two known polymorphisms,c.888 + 108 C> T (rs2953000) and c.888 +118 G>T (rs2952999),was detected in the flanking of the indel mutation in the patient and her father.Sequencing chromatogram for the family indicates that above changes are located on the same chromosome.Conclusion The c.789_790delAGinsT,as a de novo mutation occurring on the paternally derived chromosome,is most likely to be causative for the disease.Compared with Sanger sequencing,targeted next-generation sequencing is more efficient and can dramatically reduce the cost for the genetic testing of NF-1.%目的 对1例临床拟诊为神经纤维瘤Ⅰ型(neurofibromatosis type 1,NF-1)患者进行致病基因突变研究.方法 通过探针杂交富集患者神经纤维蛋白1 (neurofibromin 1,NF1)基因的全部编码区外显子及其旁侧序列进行高通量测序确定可疑突变,并用Sanger测序法对核心家系成员的相应目标基因区域进行测序验证.结果 在患者NF1基因的第8外显子检出一插入/缺失型突变(indel)c.789790delAGinsT(p.K263Nfs* 18),造成突变点后的三联密码子阅读框发生改变而导致蛋白质翻译的提前终止.其表型正常父母均无此改变.在患者突变点下游第8内含子中还检出两个源自父亲的杂合多态性改变c.888+ 108C>T(rs2953000)和c.888+ 118G>T(rs2952999

  1. Molecular Regulation of Endothelial Cells by NF-1

    Science.gov (United States)

    2013-01-01

    33 1 Introduction: NF1 and Vascular Disease Mutations in the NF1 gene cause Neurofibromatosis type 1, an autosomal dominant...to increase in the population(McClatchey 2007). NF1 has variable clinical manifestations. Most commonly changes in skin pigmentation (café au-lait...Importantly, a significant clinical manifestation of NF1 disease can include vascular disease. Patients with NF1 disease make up a significant portion

  2. The NF1 gene revisited – from bench to bedside

    OpenAIRE

    Yap, Yoon-Sim; McPherson, John R.; Ong, Choon-Kiat; Rozen, Steven G.; Teh, Bin-Tean; Lee, Ann SG; Callen, David F.

    2014-01-01

    Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. The gene product neurofibromin is a negative regulator of the Ras cellular proliferation pathway, and also exerts tumour suppression via other mechanisms. Recent next-generation sequencing projects have revealed somatic NF1 aberrations in various sporadic tumours. NF1 plays a critical role in a wide range of tumours. NF1 alterations appear to b...

  3. Skeletal Complications in Neurofibromatosis Type 1: the Role of Neurofibromin Haploinsufficiency in Defective Skeletal Remodeling and Bone Healing in NF1

    Science.gov (United States)

    2009-01-01

    nutritional basis for congenital skeletal dysplasiae . Cell Metab 4:441-451. 3. Aliprantis, A.O., Walsh, N.C., McHugh, K.P., Gravallese, E., and Glimcher...proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis, pseudoarthrosis, and sphenoid bone dysplasia

  4. Magnetic resonance diffusion tensor imaging (MRDTI) of the optic nerve and optic radiations at 3T in children with neurofibromatosis type I (NF-1)

    Energy Technology Data Exchange (ETDEWEB)

    Filippi, Christopher G.; Nickerson, Joshua P. [University of Vermont School of Medicine-FAHC, Department of Radiology, Burlington, VT (United States); Bos, Aaron [University of Vermont School of Medicine, Burlington, VT (United States); Salmela, Michael B. [University of Minnesota School of Medicine, Department of Radiology, Minneapolis, MN (United States); Koski, Chris J. [James Madison University, Department of Political Sciences, Harrisonburg, VA (United States); Cauley, Keith A. [University of Massachusetts Memorial Medical Center, Department of Radiology, Worcester, MA (United States)

    2012-02-15

    Optic pathway glioma (OPG) is a characteristic hallmark of neurofibromatosis type I (NF-I). To evaluate the feasibility of magnetic resonance diffusion tensor imaging (MRDTI) at 3T to detect abnormalities of the optic nerves and optic radiations in children with NF-I. 3-T MRDTI was prospectively performed in 9 children with NF-I (7 boys, 2 girls, average age 7.8 years, range 3-17 years) and 44 controls (25 boys, 19 girls, average age 8.1 years, range 3-17 years). Fractional anisotropy (FA) and mean diffusivity were determined by region-of-interest analysis for the optic nerves and radiations. Statistical analysis compared controls to NF-I patients. Two NF-I patients had bilateral optic nerve gliomas, three had chiasmatic gliomas and four had unidentified neurofibromatosis objects (UNOs) along the optic nerve pathways. All NF-I patients had statistically significant decreases in FA and elevations in mean diffusivity in the optic nerves and radiations compared to age-matched controls. MRDTI can evaluate the optic pathways in children with NF-I. Statistically significant abnormalities were detected in the diffusion tensor metrics of the optic nerves and radiations in children with NF-I compared to age-matched controls. (orig.)

  5. Multiple roles of NF1 in the melanocyte lineage.

    Science.gov (United States)

    Larribère, Lionel; Utikal, Jochen

    2016-07-01

    NF1 is a tumour suppressor gene, germline mutations of which lead to neurofibromatosis type 1 syndrome. Patients develop benign tumours from several types of cells including neural crest-derived cells. NF1 somatic mutations also occur in 15% of sporadic melanoma, a cancer originating from melanocytes. Evidence now suggests the involvement of NF1 mutations in melanoma resistance to targeted therapies. Although NF1 is ubiquitously expressed, genetic links between NF1 and genes involved in melanocyte biology have been described, implying the lineage-specific mechanisms. In this review, we summarize and discuss the latest advances related to the roles of NF1 in melanocyte biology and in cutaneous melanoma.

  6. Identification of large NF1 duplications reciprocal to NAHR-mediated type-1 NF1 deletions.

    Science.gov (United States)

    Kehrer-Sawatzki, Hildegard; Bengesser, Kathrin; Callens, Tom; Mikhail, Fady; Fu, Chuanhua; Hillmer, Morten; Walker, Martha E; Saal, Howard M; Lacassie, Yves; Cooper, David N; Messiaen, Ludwine

    2014-12-01

    Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events. © 2014 WILEY PERIODICALS, INC.

  7. The Handwriting Performance of Children with NF1

    Science.gov (United States)

    Gilboa, Yafit; Josman, Naomi; Fattal-Valevski, Aviva; Toledano-Alhadef, Hagit; Rosenblum, Sara

    2010-01-01

    The objective of this study was to analyze the process and product of handwriting among children with Neurofibromatosis Type 1 (NF1) in comparison to those of Typically Developing (TD) children. Children with NF1 are at risk for some cognitive deficits, a wide range of deficits in perceptual skills and, motor and visual-motor integration skills…

  8. The NF1 gene in tumor syndromes and melanoma.

    Science.gov (United States)

    Kiuru, Maija; Busam, Klaus J

    2017-02-01

    Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, ie, RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.

  9. Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours

    NARCIS (Netherlands)

    Bottillo, Irene; Ahiquist, Terje; Brekke, Helge; Danielsen, Stine A.; van den Berg, Eva; Mertens, Fredrik; Lothe, Ragnhild A.; Dallapiccola, Bruno

    2009-01-01

    Malignant peripheral nerve sheath tumours (MPNSTs) are a malignancy occurring with increased frequency in patients with neurofibromatosis type 1 (NF1). In contrast to the well-known spectrum of germline NF1 mutations, the information on somatic mutations in MPNSTs is limited. In this study, we scree

  10. [Eye involvement in neurofibromatosis].

    Science.gov (United States)

    Baier, M; Pitz, S

    2016-05-01

    Neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) are characterized by an autosomal dominant pattern of inheritance with irregular penetrance and a broad spectrum of different clinical phenotypes. There are large variations in the age of onset, progression and prognosis. Symptoms are often manifested early in childhood. Characteristics which the two main forms NF1 and NF2 have in common are a positive family history, characteristic skin alterations, such as café au lait macules, axillary or inguinal freckling and neural tumors such as neurofibroma and optic glioma (NF1) as well as (bilateral) vestibular schwannomas (NF2). An interdisciplinary cooperation is necessary for the diagnostics and therapy.

  11. Up-regulation of specific NF1 gene transcripts in sporadic pilocytic astrocytomas

    NARCIS (Netherlands)

    Platten, M; Giordano, MJ; Dirven, CMF; Gutmann, DH; Louis, DN

    1996-01-01

    Pilocytic astrocytomas of the optic nerve (optic nerve gliomas) are closely associated with neurofibromatosis 1 (NF1), and allelic losses of the NF1 gene region on chromosome 17q occur in sporadic pilocytic astrocytomas. We therefore hypothesized that the NF1 gene nets as a tumor suppressor gene in

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

    OpenAIRE

    Lasater, Elisabeth A.; Bessler, Waylan K.; Mead, Laura E.; Horn, Whitney E.; Clapp, D. Wade; Conway, Simon J; Ingram, David A.; Li, Fang

    2008-01-01

    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 biochemi...

  13. A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors

    Energy Technology Data Exchange (ETDEWEB)

    Cappione, A.J.; French, B.L.; Skuse, G.R. [Univ. of Rochester School of Medicine and Dentistry, NY (United States)

    1997-02-01

    Neurofibromatosis type I (NF1) is a common disorder that predisposes to neoplasia in tissues derived from the embryonic neural crest. The NF1 gene encodes a tumor suppressor that most likely acts through the interaction of its GTPase-activating protein (GAP)-related domain (GRD) with the product of the ras protooncogene. We have previously identified a site in the NF1 mRNA, within the first half of the NF1 GRD, which undergoes base-modification editing. Editing at that site changes a C to a U, thereby introducing an in-frame stop codon. NF1 RNA editing has been detected in all cell types studied, to date. In order to investigate the role played by editing in NF1 tumorigenesis, we analyzed RNA from 19 NF1 and 4 non-NF1 tumors. We observed varying levels of NF1 mRNA editing in different tumors, with a higher range of editing levels in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas have an intermediate range of levels of NF1 mRNA editing. We also compared tumor and nontumor tissues from several NF1 individuals, to determine the extent of variability present in the constitutional levels of NF1 mRNA editing and to determine whether higher levels are present in tumors. The constitutional levels of NF1 mRNA editing varied slightly but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggest that inappropriately high levels of NF1 mRNA editing does play a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor. 24 refs., 4 figs., 2 tabs.

  14. NF1 Signal Transduction and Vascular Dysfunction

    Science.gov (United States)

    2015-05-01

    as well as clinically available pharmaceuticals , we are determining the critical regulatory pathways that drive the changes seen following the loss of...loss in the adult endothelium and can serve as a model system for investigation of both cardiovascular effects and the tumor microenvironment. Body: Aim...Korf, B. R. (2002). Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med 4, 105-111. Munchhof, A. M

  15. The NF1 gene revisited - from bench to bedside.

    Science.gov (United States)

    Yap, Yoon-Sim; McPherson, John R; Ong, Choon-Kiat; Rozen, Steven G; Teh, Bin-Tean; Lee, Ann S G; Callen, David F

    2014-08-15

    Neurofibromatosis type 1 (NF1) is a relatively common tumour predisposition syndrome related to germline aberrations of NF1, a tumour suppressor gene. The gene product neurofibromin is a negative regulator of the Ras cellular proliferation pathway, and also exerts tumour suppression via other mechanisms. Recent next-generation sequencing projects have revealed somatic NF1 aberrations in various sporadic tumours. NF1 plays a critical role in a wide range of tumours. NF1 alterations appear to be associated with resistance to therapy and adverse outcomes in several tumour types. Identification of a patient's germline or somatic NF1 aberrations can be challenging, as NF1 is one of the largest human genes, with a myriad of possible mutations. Epigenetic factors may also also contribute to inadequate levels of neurofibromin in cancer cells. Clinical trials of NF1-based therapeutic approaches are currently limited. Preclinical studies on neurofibromin-deficient malignancies have mainly been on malignant peripheral nerve sheath tumour cell lines or xenografts derived from NF1 patients. However, the emerging recognition of the role of NF1 in sporadic cancers may lead to the development of NF1-based treatments for other tumour types. Improved understanding of the implications of NF1 aberrations is critical for the development of novel therapeutic strategies.

  16. Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway

    OpenAIRE

    Stansfield, Brian K.; Bessler, Waylan K.; Mali, Raghuveer; Mund, Julie A.; Downing, Brandon; Li, Fang; Sarchet, Kara N.; Distasi, Matthew R.; Conway, Simon J; Kapur, Reuben; Ingram, David A.

    2012-01-01

    Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf...

  17. 一个Ⅰ型神经纤维瘤家系的基因突变分析%NF1 mutation analysis in a Chinese family with neuro-fibromatosis type Ⅰ

    Institute of Scientific and Technical Information of China (English)

    黄颖浩; 杨琴波; 邓云华; 余念文; 王擎; 刘木根

    2008-01-01

    鉴定了一个中国家庭中的常染色体显性遗传病-Ⅰ型神经纤维瘤,通过连锁分析和NF1基因测序,发现该家系中NF1疾病的致病基因与NF1基因连锁,并在NF1基因上发现了一个无义突变G1336X,该突变导致神经纤维蛋白从C末端截断1 483个氨基酸残基.G1336X突变在该家系中与疾病共分离,但家系中的正常成员未能检出,表明NF1基因的G1336X的突变是引起该家族患NF1疾病的原因.该突变是第一次在中国NF1疾病人群中报道.

  18. Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

    NARCIS (Netherlands)

    J. Wu (Jianqiang); J.P. Williams (Jon); T.A. Rizvi (Tilat); J.J. Kordich (Jennifer); D. Witte (David); D.N. Meijer (Dies); A.O. Stemmer-Rachamimov (Anat); J.A. Cancelas (Jose); N. Ratner (Nancy)

    2008-01-01

    textabstractNeurofibromatosis type 1 (Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5

  19. Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

    NARCIS (Netherlands)

    J. Wu (Jianqiang); J.P. Williams (Jon); T.A. Rizvi (Tilat); J.J. Kordich (Jennifer); D. Witte (David); D.N. Meijer (Dies); A.O. Stemmer-Rachamimov (Anat); J.A. Cancelas (Jose); N. Ratner (Nancy)

    2008-01-01

    textabstractNeurofibromatosis type 1 (Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5

  20. Neurofibromatosis 2

    Directory of Open Access Journals (Sweden)

    Abhijit M Patil

    2015-01-01

    Full Text Available Neurofibromatosis 2 is a rare autosomal dominant neurocutaneous disorder classically characterized by bilateral acoustic schwannomas. Multiple other central, as well as peripheral central nervous system neoplasms as meningiomas and ependymomas, are also associated. We present here a case of 18-year-old female with bilateral hearing loss. Magnetic resonance imaging (MRI of the brain and spine showed multiple intracranial and intra-spinal neoplasms. Bilateral large acoustic and other cranial nerve schwannomas, along with multiple spinal neurofibromas were present. Based on these MRI findings a diagnosis of neurofibromatosis was made.

  1. Immortalization of human normal and NF1 neurofibroma Schwann cells.

    Science.gov (United States)

    Li, Hua; Chang, Lung-Ji; Neubauer, Debbie R; Muir, David F; Wallace, Margaret R

    2016-10-01

    Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.

  2. Behavioral and Sleep Disorders in Neurofibromatosis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-04-01

    Full Text Available The behavior and sleep patterns of 64 children (mean age 10 years 7 months with neurofibromatosis type 1 (NF1 were determined by mail and telephone questionnaire in a study at Park Hospital, University of Oxford, UK.

  3. The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond.

    Science.gov (United States)

    Welander, Jenny; Söderkvist, Peter; Gimm, Oliver

    2013-08-01

    Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome-associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent.

  4. 一个Ⅰ型神经纤维瘤病家系的基因突变分析%NF1 Mutation Analysis in a Family with Neurofibromatosis Type Ⅰ

    Institute of Scientific and Technical Information of China (English)

    李丹丹; 王进; 梁婷; 马兰茗; 刘明

    2013-01-01

    目的:Ⅰ型神经纤维瘤病是一种常见的常染色体显性遗传病,主要累及皮肤和神经系统.其临床表现多样,主要以“咖啡牛奶斑”、皮肤神经纤维瘤、虹膜Lisch结节、腋窝和腹股沟斑点为特征,Ⅰ型神经纤维瘤病由NF1基因突变所致,神经纤维瘤蛋白是NF1基因编码蛋白,是一种肿瘤抑制蛋白,可抑制细胞的过度生长.NF1基因突变不仅可导致细胞过度生长,还可增加良性及恶性肿瘤的发生风险.本研究中,我们通过基因突变分析,确定中国东北地区一个伴有先天性白内障的Ⅰ型神经纤维瘤家系NF1基因的突变位点.方法:通过聚合酶链反应(PCR)和NF1基因直接测序分析对家系中的3名患者及2名健康成员进行基因突变检测,以确定其突变位点.结果:此家系呈常染色体显性遗传.通过基因序列分析发现NF1基因第1140密码子第二个碱基呈杂合子点突变C→G,导致一个无义突变S1140X,家系中健康成员和正常对照未检测到此突变存在.结论:通过NF1基因测序分析,我们发现NF1基因的S1140X突变是引起该家系NF1疾病的致病原因,该突变导致NF1基因终止密码提前,神经纤维瘤素蛋白截短.本研究丰富了我国关于Ⅰ型神经纤维瘤病在眼科的临床表现.

  5. NF1 Is an Effector and Regulator of the GPCR Signaling in the Nervous System

    Science.gov (United States)

    2015-04-01

    1 AD______________ AWARD NUMBER: W81XWH-14-1-0074 TITLE: “NF1 Is an Effector and Regulator of the GPCR Signaling in the Nervous System ...NF1 Is an Effector and Regulator of the GPCR Signaling in the Nervous System 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kirill Martemyanov, Ph.D...strategies. 15. SUBJECT TERMS neurofibromatosis, nervous system disorders, receptor signaling mechanisms, NF1 16. SECURITY CLASSIFICATION OF: 17

  6. 一个Ⅰ型神经纤维瘤家族NF1基因18和19外显子的检测%Detection of NF1 exon 18 and 19 in a Neurofibromatosis type 1 family

    Institute of Scientific and Technical Information of China (English)

    刘晶; 周琴; 许名宗; 张贵平; 肖毅仁; 雷日华; 姚飞虹; 陈莹花; 罗桐秀

    2013-01-01

    目的 检测郴州市一个Ⅰ型神经纤维瘤家族NF1基因的18 ~ 19外显子区段是否发生突变.方法 应用PCR技术扩增NF1基因18~19外显子区段,并对PCR产物进行测序.结果 该家系的Ⅳ1患者的18外显子的一对碱基发生置换(错义突变),Ⅱ2患者的18~ 19外显子之间的内含子一对碱基发生置换,但家系中另两名患者和正常成员18 ~19外显子区段序列均正常.结论 NF1具多突变性.两处碱基置换可能与Ⅱ2和Ⅳ1患神经纤维瘤发生有关,但不是该家族引起神经纤维瘤的共享突变维点.

  7. Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein.

    NARCIS (Netherlands)

    Yang, G.; Khalaf, W.; Locht, L.; Jansen, J.H.; Gao, M.; Thompson, M.A.; Reijden, B.A. van der; Gutmann, D.H.; Delwel, R.; Clapp, D.W.; Hiebert, S.W.

    2005-01-01

    Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are

  8. No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients.

    Science.gov (United States)

    Hutter, Sonja; Piro, Rosario M; Waszak, Sebastian M; Kehrer-Sawatzki, Hildegard; Friedrich, Reinhard E; Lassaletta, Alvaro; Witt, Olaf; Korbel, Jan O; Lichter, Peter; Schuhmann, Martin U; Pfister, Stefan M; Tabori, Uri; Mautner, Victor F; Jones, David T W

    2016-05-01

    Neurofibromatosis type 1 (NF1) is a common monogenic disorder whereby affected individuals are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs, occurring in ~15 to 20 % of cases). So far, no definite genotype-phenotype correlation determining NF1 patients at risk for tumor formation has been described, although enrichment for mutations in the 5' region of the NF1 gene in OPG patients has been suggested. We used whole exome sequencing, targeted sequencing, and copy number analysis to screen 77 unrelated NF1 patients with (n = 41) or without (n = 36; age ≥10 years) optic pathway glioma for germline NF1 alterations. We identified germline NF1 mutations in 69 of 77 patients (90 %), but no genotype-phenotype correlation was observed. Our data using a larger patient cohort did not confirm the previously reported clustering of mutations in the 5' region of the NF1 gene in patients with OPG. Thus, NF1 mutation location should not currently be used as a clinical criterion to assess the risk of developing OPGs.

  9. Motor learning in children with neurofibromatosis type I

    NARCIS (Netherlands)

    L.C. Krab (Lianne); A. de Goede-Bolder (Arja); F.J. Aarsen (Femke); H.A. Moll (Henriëtte); C.I. de Zeeuw (Chris); Y. Elgersma (Ype); J.N. van der Geest (Jos)

    2011-01-01

    textabstractThe aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed

  10. Motor learning in children with neurofibromatosis type I

    NARCIS (Netherlands)

    L.C. Krab (Lianne); A. de Goede-Bolder (Arja); F.J. Aarsen (Femke); H.A. Moll (Henriëtte); C.I. de Zeeuw (Chris); Y. Elgersma (Ype); J.N. van der Geest (Jos)

    2011-01-01

    textabstractThe aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed subs

  11. Neurofibromatosis Type 1 and Diabetes Mellitus: An Unusual Association

    Directory of Open Access Journals (Sweden)

    Bayram Ozhan

    2013-01-01

    Full Text Available Neurofibromatosis type 1 is a multisystemic disease. It may manifest as abnormalities of the nervous tissue, bones, soft tissue, or skin. Autoimmune disease associated with NF1 can be seen. Diabetes mellitus is rarely seen in association with NF1. Here, we report a case with established NF1 who also had a diagnosis of diabetes mellitus.

  12. Segmental neurofibromatosis: report of 3 cases.

    Science.gov (United States)

    Mansur, Ayşe Tülin; Göktay, Fatih; Akkaya, Ayşe Deniz; Güneş, Pembegül

    2011-01-01

    Segmental neurofibromatosis (SNF) is an uncommon variant of neurofibromatosis type 1 (NF-1) that is characterized by café au lait spots, freckles, and/or neurofibromas limited to a body segment. In this report we describe 3 adult patients with SNF who presented with only neurofibromas. Although 2 patients had no systemic involvement, the third patient had hypertrophic cardiomyopathy, a cardiologic abnormality that is associated with neurofibromatosis.

  13. Neurofibromatosis presenting with a cherubism phenotype.

    NARCIS (Netherlands)

    Capelle, C.I. van; Hogeman, P.H.; Sijs-Bos, C.J.M. van der; Heggelman, B.G.; Idowu, B.; Slootweg, P.J.; Wittkampf, A.R.M.; Flanagan, A.M.

    2007-01-01

    We report on a child who presented clinical manifestations of both neurofibromatosis type 1 (NF1) and cherubism. With genetic testing, we found a mutation in the NF-1 gene, confirming the neurocutaneous disorder. Histology when correlated with radiological evaluation of a mandibular biopsy was

  14. Neurofibromatosis presenting with a cherubism phenotype.

    NARCIS (Netherlands)

    Capelle, C.I. van; Hogeman, P.H.; Sijs-Bos, C.J.M. van der; Heggelman, B.G.; Idowu, B.; Slootweg, P.J.; Wittkampf, A.R.M.; Flanagan, A.M.

    2007-01-01

    We report on a child who presented clinical manifestations of both neurofibromatosis type 1 (NF1) and cherubism. With genetic testing, we found a mutation in the NF-1 gene, confirming the neurocutaneous disorder. Histology when correlated with radiological evaluation of a mandibular biopsy was consi

  15. Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway.

    Science.gov (United States)

    Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer; Mund, Julie A; Downing, Brandon; Li, Fang; Sarchet, Kara N; DiStasi, Matthew R; Conway, Simon J; Kapur, Reuben; Ingram, David A

    2013-03-01

    Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) in bone marrow cells enhances neointima formation following arterial injury. Macrophages infiltrate Nf1(+/-) neointimas, and NF1 patients have increased circulating inflammatory monocytes in their peripheral blood. Therefore, we tested the hypothesis that heterozygous inactivation of Nf1 in myeloid cells is sufficient for neointima formation. Specific ablation of a single copy of the Nf1 gene in myeloid cells alone mobilizes a discrete pro-inflammatory murine monocyte population via a cell autonomous and gene-dosage dependent mechanism. Furthermore, lineage-restricted heterozygous inactivation of Nf1 in myeloid cells is sufficient to reproduce the enhanced neointima formation observed in Nf1(+/-) mice when compared with wild-type controls, and homozygous inactivation of Nf1 in myeloid cells amplified the degree of arterial stenosis after arterial injury. Treatment of Nf1(+/-) mice with rosuvastatin, a stain with anti-inflammatory properties, significantly reduced neointima formation when compared with control. These studies identify neurofibromin-deficient myeloid cells as critical cellular effectors of Nf1(+/-) neointima formation and propose a potential therapeutic for NF1 cardiovascular disease.

  16. Facial Plexiform neurofibromatosis in a patient with neurofibromatosis type1: a case report

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    Iffat Hassan

    2012-01-01

    Full Text Available Plexiform neurofibroma is a poorly circumscribed, diffuse enlargement of neural sheets that typically involves major nerve trunks of the head and neck region because of the rich innervations of this area. It is a benign tumor and is a virtually pathognomonic and often disabling feature of neurofibromatosis type 1 (NF-1 or Von Recklinghausen’s disease. We hereby report a case of facial neurofibroma in an adult female with neurofibromatosis type 1 (NF-1.

  17. Spontaneous Rupture of Recurrent Gastrointestinal Stromal Tumor Associated with Neurofibromatosis Type 1

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    Shin-Mae Wang

    2005-11-01

    Full Text Available The incidence of gastrointestinal stromal tumor (GIST among neurofibromatosis type 1 (NF-1 patients is approximately 3.9–25%, and this relationship is generally considered to be non-coincidental. We report a patient with NF-1 who underwent laparotomy 3 times due to recurrent intra-abdominal tumor rupture with internal bleeding in the space of 13 years. The pathologic diagnoses were schwannoma, malignant peripheral nerve sheath tumor and GIST. Because of the similar histologic features of these tumors, we considered them to be of the same nature. Immunohistochemical staining can help in the differential diagnosis. We suggest that NF-1 patients with gastrointestinal symptoms receive further survey to rule out GISTs.

  18. Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis.

    Science.gov (United States)

    Rhodes, Steven D; Yang, Hao; Dong, Ruizhi; Menon, Keshav; He, Yongzheng; Li, Zhaomin; Chen, Shi; Staser, Karl W; Jiang, Li; Wu, Xiaohua; Yang, Xianlin; Peng, Xianghong; Mohammad, Khalid S; Guise, Theresa A; Xu, Mingjiang; Yang, Feng-Chun

    2015-10-01

    Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in-function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.

  19. NEUROFIBROMATOSIS TYPE I: CASE REPORT

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    Neha

    2014-12-01

    Full Text Available : Neurofibromatosis (NF is a term that has been applied to a variety of related syndromes, characterized by neuro ectodermal tumors arising within multiple organs and autosomal-dominant inheritance. Neurofibromatosis type I(NF-1, known as well as Recklinghausen’s disease, we have presented a case report of 10 year old boy with complain of scalp swelling on right postero-lateral aspect of scalp with multiple flat, hypo pigmented macule on back, neck. On radiology work up including MRI there were multiple plexiform neuroibromas, multiple non-neoplastic hamartomatous lesion suggestive of neurofibromatosis type.

  20. Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene

    Directory of Open Access Journals (Sweden)

    Gustavo Fernandes

    2014-01-01

    Full Text Available Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1 which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689 flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689 in the interphases analyzed and two signals (RP5-1002G3conRP5-92689 in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders.

  1. Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation.

    Science.gov (United States)

    Bessler, Waylan K; Kim, Grace; Hudson, Farlyn Z; Mund, Julie A; Mali, Raghuveer; Menon, Keshav; Kapur, Reuben; Clapp, D Wade; Ingram, David A; Stansfield, Brian K

    2016-03-15

    Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.

  2. Testing Current and Developing Novel Therapies for NF1-Mutant Sarcomas in a Genetically Engineered Mouse Model

    Science.gov (United States)

    2015-04-01

    1   AWARD NUMBER: W81XWH-14-1-0067 TITLE: Testing Current and Developing Novel Therapies for NF1 -Mutant Sarcomas in a Genetically Engineered...Mar 2014 - 14 Mar 2015 4. TITLE AND SUBTITLE Testing Current and Developing Novel Therapies for NF1 - Mutant Sarcomas in a Genetically Engineered...Patients with Neurofibromatosis type 1 ( NF1 ) are at increased risk for developing malignant tumors of the connective tissue called soft-tissue sarcomas

  3. NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model.

    Science.gov (United States)

    Larribere, Lionel; Wu, Huizi; Novak, Daniel; Galach, Marta; Bernhardt, Mathias; Orouji, Elias; Weina, Kasia; Knappe, Nathalie; Sachpekidis, Christos; Umansky, Ludmila; Beckhove, Philipp; Umansky, Viktor; De Schepper, Sofie; Kaufmann, Dieter; Ballotti, Robert; Bertolotto, Corine; Utikal, Jochen

    2015-07-01

    Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) -induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage.

  4. Cardiac characterization of 16 patients with large NF1 gene deletions.

    Science.gov (United States)

    Nguyen, R; Mir, T S; Kluwe, L; Jett, K; Kentsch, M; Mueller, G; Kehrer-Sawatzki, H; Friedman, J M; Mautner, V-F

    2013-10-01

    The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age- and sex-matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non-deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

  5. Zebrafish as a Model to Study NF1-Associated Learning Deficits

    Science.gov (United States)

    2016-07-01

    screening libraries of bioactive small molecules. 15. SUBJECT TERMS Neurofibromatosis; zebrafish; NF1; cAMP; Ras; learning; memory 16. SECURITY ...Hannan, F., Bernards, A., and Zhong, Y. (1997). Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuro - peptides. Science...a mouse model of neuro - fibromatosis type 1. Curr. Biol. 15, 1961–1967. Liao, J.K., and Laufs, U. (2005). Pleiotropic effects of statins. Annu. Rev

  6. Emerging genotype-phenotype relationships in patients with large NF1 deletions.

    Science.gov (United States)

    Kehrer-Sawatzki, Hildegard; Mautner, Victor-Felix; Cooper, David N

    2017-04-01

    The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16-26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8-13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype-phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

  7. Clustering of mutations in the 5' tertile of the NF1 gene in Slovakia patients with optic pathway glioma.

    Science.gov (United States)

    Bolcekova, A; Nemethova, M; Zatkova, A; Hlinkova, K; Pozgayova, S; Hlavata, A; Kadasi, L; Durovcikova, D; Gerinec, A; Husakova, K; Pavlovicova, Z; Holobrada, M; Kovacs, L; Ilencikova, D

    2013-01-01

    Optic pathway gliomas (OPG) occur in 15% of patients with neurofibromatosis type 1 (NF1; OMIM 162200). Genotype-phenotype correlations in patients with NF1 may help to determine the risk group for developing complications such as OPG in coincidence with other NF1.features. We evaluated 52 patients with NF1 (25 with OPG and 27 without OPG). All subjects underwent a clinical examination focused on neurofibromatosis type 1 and molecular diagnostics of NF1 gene using protocol based on RNA analysis confirming the diagnosis of NF1. In the group with OPG patients, there was a significantly higher incidence of freckling (P=0.017), neurofibromatosis bright objects (NBO) (P=0.0038), compared to the group without OPG. The differences between the groups with respect to Lisch nodules were on the borderline of statistical significance (P=0.088). The frequency of neurofibromas in the group with OPG was not significant (P=0.9). From all patients with the mutation localized in the first tertile of the NF1 gene majority (71%) had optic glioma compared to individuals who didn't have the OPG 29% (P=0.0049). Our results present the clustering of mutations in the 5'tertile of NF1 gene in patients with optic nerve glioma and suggest higher incidence of freckling and neurofibromatosis brain objects in these patients. Molecular analysis of NF1 gene is important part in complex management of NF1 patients and contributes to a better understanding of clinical picture of NF1 patients. .

  8. CNS Tumors in Neurofibromatosis.

    Science.gov (United States)

    Campian, Jian; Gutmann, David H

    2017-07-20

    Neurofibromatosis (NF) encompasses a group of distinct genetic disorders in which affected children and adults are prone to the development of benign and malignant tumors of the nervous system. The purpose of this review is to discuss the spectrum of CNS tumors arising in individuals with NF type 1 (NF1) and NF type 2 (NF2), their pathogenic etiologies, and the rational treatment options for people with these neoplasms. This article is a review of preclinical and clinical data focused on the treatment of the most common CNS tumors encountered in children and adults with NF1 and NF2. Although children with NF1 are at risk for developing low-grade gliomas of the optic pathway and brainstem, individuals with NF2 typically manifest low-grade tumors affecting the cranial nerves (vestibular schwannomas), meninges (meningiomas), and spinal cord (ependymomas). With the identification of the NF1 and NF2 genes, molecularly targeted therapies are beginning to emerge, as a result of a deeper understanding of the mechanisms underlying NF1 and NF2 protein function. As we enter into an era of precision oncology, a more comprehensive awareness of the factors that increase the risk of developing CNS cancers in affected individuals, coupled with a greater appreciation of the cellular and molecular determinants that maintain tumor growth, will undoubtedly yield more effective therapies for these cancer predisposition syndromes.

  9. Mosaic generalized neurofibromatosis 1: report of two cases.

    Science.gov (United States)

    Hardin, Jori; Behm, Allan; Haber, Richard M

    2014-01-01

    We report two cases of mosaic generalized neurofibromatosis 1 (NF1) and review the history of the classification of segmental neurofibromatosis (SNF; Ricardi type NF-V). Somatic mutations giving rise to limited disease, such as segmental neurofibromatosis are manifestations of mosaicism. If the mutation occurs before tissue differentiation, the clinical phenotype will be generalized disease. Mutations that occur later in development give rise to disease that is confined to a single region. Segmental neurofibromatosis is caused by a somatic mutation of neurofibromatosis type 1, and should not be regarded as a distinct entity from neurofibromatosis 1. Cases previously referred to as unilateral or bilateral segmental neurofibromatosis are now best referred to as mosaic generalized or mosaic localized neurofibromatosis 1.

  10. Late-Onset Glioma with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-10-01

    Full Text Available The frequency of symptomatic nonoptic pathway brain tumors in adolescents and adults known to have neurofibromatosis type 1 (NF1 was determined from the National Neurofibromatosis Foundation International Database (NNFFID in a study at Washington University School of Medicine, St Louis, MO.

  11. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1.

    NARCIS (Netherlands)

    Vandenbroucke, I; Doorn, van R.; Callens, T; Cobben, J.M.; Starink, T.M.; Messiaen, L

    2004-01-01

    Patients with typical features of neurofibromatosis type 1 (NF1) limited to a specific body segment are usually referred to as having "segmental NF1", which is generally assumed to be the result of somatic mosaicism for a NF1 mutation. Mosaicism has also been demonstrated at the molecular level in s

  12. Neurofibromatosis type 1 associated low grade gliomas : A comparison with sporadic low grade gliomas

    NARCIS (Netherlands)

    Helfferich, Jelte; Nijmeijer, Ronald; Brouwer, Oebele F.; Boon, Maartje; Fock, Annemarie; Hoving, Eelco W.; Meijer, Lisethe; den Dunnen, Wilfred F. A.; de Bont, Eveline S. J. M.

    2016-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including cafe-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which

  13. Potential Influences on Mathematical Difficulties in Children and Adolescents with Neurofibromatosis, Type 1

    Science.gov (United States)

    Moore, Bartlett D.

    2009-01-01

    Neurofibromatosis, type 1 (NF-1) is a common genetic disorder affecting 1 in 3,500-4,000 individuals in the world. Mutations of the NF-1 gene produce a myriad of physical, medical, and psychological manifestations. Although there is a very high degree of variability in the manifestations between individuals with NF-1, the majority of children and…

  14. Down syndrome and neurofibromatosis: a case report.

    Science.gov (United States)

    Schaffer, Rebecca; Goss, Lindsay; Romer, Maureen Munnelly; Kalamchi, Sabah

    2014-01-01

    The dental management of a patient presenting with both Down syndrome and neurofibromatosis type 1 (NF1) has not previously been described well in the dental literature. A 20-year-old male with both of these genetic anomalies sought comprehensive treatment at the Special Needs Dental clinic at the Arizona School of Dentistry and Oral Health. He presented with multiple decayed surfaces, retained primary teeth, and intra/extra oral soft tissue tumors. Dental extractions and tumor reduction surgery took place at a private dental office due to the need for intravenous sedation for patient management. At the conclusion of the patient's -treatment, while his oral health was improved, there was little improvement in the facial aesthetics of his case. Coordinating care among health care providers in a patient with Trisomy 21 and NF1 is essential for a reliable and predictable outcome. However, as neurofibromas are often known to recur, the treatment risks and advantages should be reviewed prior to surgical intervention. © 2013 Special Care Dentistry Association and Wiley Periodicals, Inc.

  15. Mouse Models of Neurofibromatosis 1 and 2

    Directory of Open Access Journals (Sweden)

    David H. Gutmann

    2002-01-01

    Full Text Available The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1 are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2 develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.

  16. Speech Disorders in Neurofibromatosis Type 1: A Sample Survey

    Science.gov (United States)

    Cosyns, Marjan; Vandeweghe, Lies; Mortier, Geert; Janssens, Sandra; Van Borsel, John

    2010-01-01

    Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder with an estimated prevalence of two to three cases per 10 000 population. While the physical characteristics have been well documented, speech disorders have not been fully characterized in NF1 patients. Aims: This study serves as a pilot to identify key…

  17. Speech Disorders in Neurofibromatosis Type 1: A Sample Survey

    Science.gov (United States)

    Cosyns, Marjan; Vandeweghe, Lies; Mortier, Geert; Janssens, Sandra; Van Borsel, John

    2010-01-01

    Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder with an estimated prevalence of two to three cases per 10 000 population. While the physical characteristics have been well documented, speech disorders have not been fully characterized in NF1 patients. Aims: This study serves as a pilot to identify key…

  18. Personality profiles of children and adolescents with neurofibromatosis type 1

    NARCIS (Netherlands)

    Prinzie, P.; Descheemaeker, M.J.; Vogels, A.; Cleymans, T.; Haselager, G.J.T.; Curfs, L.M.G; Hellinckx, W.; Onghena, P.; Legius, E.; Lieshout, C.F.M. van; Fryns, J.P.

    2003-01-01

    The personality profile of 44 youngsters (24 males, 20 females; mean age 11 years, 3 months) with neurofibromatosis type 1 (NF1) was compared with a group of 220 non-NF1 control youngsters (matched on age and gender). Personality characteristics of each youngster were rated by both parents, using th

  19. Cerebellar pleomorphic xanthoastrocytoma in a patient with neurofibromatosis type 1

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    Naidich, M.J.; Walker, M.T.; Han, G. [Northwestern University Feinberg School of Medicine, Department of Radiology, Chicago, Illinois (United States); Northwestern Memorial Hospital, Chicago, IL (United States); Gottardi-Littell, N.R. [Northwestern Memorial Hospital, Chicago, IL (United States); Northwestern University Feinberg School of Medicine, Department of Pathology, Chicago, Illinois (United States); Chandler, J.P. [Northwestern Memorial Hospital, Chicago, IL (United States); Northwestern University Feinberg School of Medicine, Department of Neurological Surgery, Chicago, Illinois (United States)

    2004-10-01

    We describe a case of cerebellar pleomorphic xanthoastrocytoma (PXA) occurring in a patient with neurofibromatosis type 1 (NF1). The histomorphology of this uncommon glial (astrocytic) neoplasm is discussed. The occurrence of this tumor within the posterior fossa is extremely rare. To our knowledge, this is the first reported case of a cerebellar PXA in a patient with NF1. (orig.)

  20. Autism Spectrum Disorder Profile in Neurofibromatosis Type I

    Science.gov (United States)

    Garg, Shruti; Plasschaert, Ellen; Descheemaeker, Mie-Jef; Huson, Susan; Borghgraef, Martine; Vogels, Annick; Evans, D. Gareth; Legius, Eric; Green, Jonathan

    2015-01-01

    Neurofibromatosis Type 1 (NF1) is a common autosomal dominant single-gene disorder, in which the co-occurrence of autism spectrum disorder (ASD) has attracted considerable research interest recently with prevalence estimates of 21-40%. However, detailed characterization of the ASD behavioral phenotype in NF1 is still lacking. This study…

  1. Articulation in Schoolchildren and Adults with Neurofibromatosis Type 1

    Science.gov (United States)

    Cosyns, Marjan; Mortier, Geert; Janssens, Sandra; Bogaert, Famke; D'Hondt, Stephanie; Van Borsel, John

    2012-01-01

    Several authors mentioned the occurrence of articulation problems in the neurofibromatosis type 1 (NF1) population. However, few studies have undertaken a detailed analysis of the articulation skills of NF1 patients, especially in schoolchildren and adults. Therefore, the aim of the present study was to examine in depth the articulation skills of…

  2. Generalized metabolic bone disease in Neurofibromatosis type I

    Science.gov (United States)

    Skeletal abnormalities are a recognized component of Neurofibromatosis type I (NF1), but a generalized metabolic bone defect in NF1 has not been fully characterized thus far. The purpose of this study was to characterize at the densitometric, biochemical, and pathological level the bone involvement ...

  3. Modeling Cognitive Dysfunction in Neurofibromatosis-1

    OpenAIRE

    Diggs-Andrews, Kelly A.; David H Gutmann

    2013-01-01

    Cognitive dysfunction, including significant impairments in learning, behavior, and attention, is found in over 10% of children in the general population. However, in the common inherited cancer predisposition syndrome, Neurofibromatosis type 1 (NF1), the prevalence of these cognitive deficits approaches 70%. As a monogenic disorder, NF1 provides a unique genetic tool to identify and mechanistically dissect the molecular and cellular bases underlying cognitive dysfunction. In this review, we ...

  4. Gonosomal mosaicism for an NF1 deletion in a sperm donor

    DEFF Research Database (Denmark)

    Callum, P; Messiaen, L M; Bower, P V

    2012-01-01

    Screening of gamete donors can reduce but cannot eliminate the risks for medical problems in donor-conceived offspring. We present a case of gonosomal mosaicism discovered in an anonymous sperm donor after receiving two reports of neurofibromatosis type 1 (NF1) in donor-conceived offspring...

  5. Optimizing biologically targeted clinical trials for neurofibromatosis.

    Science.gov (United States)

    Gutmann, David H; Blakeley, Jaishri O; Korf, Bruce R; Packer, Roger J

    2013-04-01

    The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy.

  6. Neurofibromatosis 2

    Science.gov (United States)

    NF2; Bilateral acoustic neurofibromatosis; Central bilateral acoustic NF ... Evans DG. Neurofibromatosis 2. GeneReviews . Seattle, WA; University of Washington; 2011:8. www.ncbi.nlm.nih.gov/books/NBK1201/ . Accessed: October ...

  7. NF1 and Neurofibromin: Emerging Players in the Genetic Landscape of Desmoplastic Melanoma.

    Science.gov (United States)

    Mahalingam, Meera

    2017-01-01

    Neurofibromatosis type I (NF1), a monogenic disorder with an autosomal dominant mode of inheritance, is caused by alterations in the NF1 gene which codes for the protein neurofibromin. Functionally, NF1 is a tumor suppressor as it is GTPase-activating protein that negatively regulates the MAPK pathway. More recently, much attention has focused on the role of NF1 and neurofibromin in melanoma as mutations in NF1 have been found to constitute 1 of the 4 distinct genomic categories of melanoma, with the other 3 comprising BRAF, NRAS, and "triple-wild-type" subtypes. In this review, we parse the literature on NF1 and neurofibromin with a view to clarifying and gaining a better understanding of their precise role/s in melanomagenesis. We begin with a historic overview, followed by details regarding structure and function and characterization of neural crest development as a model for genetic reversion in neoplasia. Melanogenesis in NF1 sets the stage for the discussion on the roles of NF1 and neurofibromin in neural crest-derived neoplasms including melanoma with particular emphasis on NF1 and neurofibromin as markers of melanocyte dedifferentiation in desmoplastic melanoma.

  8. Neurofibromatosis: part 2--clinical management.

    Science.gov (United States)

    Batista, Pollyanna Barros; Bertollo, Eny Maria Goloni; Costa, Danielle de Souza; Eliam, Lucas; Cunha, Karin Soares Gonçalves; Cunha-Melo, José Renan; Darrigo Junior, Luiz Guilherme; Geller, Mauro; Gianordoli-Nascimento, Ingrid Faria; Madeira, Luciana Gonçalves; Mendes, Hérika Martins; Miranda, Débora Marques de; Mata-Machado, Nikolas Andre; Morato, Eric Grossi; Pavarino, Érika Cristina; Pereira, Luciana Baptista; Rezende, Nilton Alves de; Rodrigues, Luíza de Oliveira; Sette, Jorge Bezerra Cavalcanti

    2015-06-01

    Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SCH). NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

  9. Large deletion in the NF1 gene associated with dysmorphism

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, H.E.; Maynard, J.; Sourour, E. [University Hospital of Wales, Cardiff (United Kingdom)] [and others

    1994-09-01

    Neurofibromatosis type 1 is an autosomal dominant disorder with a prevalence of 1 in 3000. The major clinical features of the disease include cafe-au-lait spots, neurofibromas, Lisch nodules and auxillary freckling. Six sporadic NF1 patients with dysmorphism and intellectual impairment have been described to have a large deletion extending beyond the NF1 gene. We report another spordiac NF1 patient with severe developmental delay, early growth failure and dysmorphism (not Noonan-like) associated with a large deletion involving the NF1 gene. A panel of 12 polymorphic DNA markers within 4 cM of the NF1 gene were used to screen for the NF1 gene rearrangements. With all the polymorphic markers, only a single band was ever observed in this affected individual. However, with DNA probe EW301 which maps to 17p, a biparental inheritance was observed. Analysis with several microsatellite markers indicated that this patient had not inherited an allele from the father. A reduction in the hybridization signal was also observed when DNA from this patient was screened with cDNAs AE25, P5, B3A, and an extragenic marker EW206, clearly indicating hemizygosity at these loci. The combined evidence of dosage reduction and biparental inheritance with DNA marker EW301 indictates that this patient has a deletion of paternal origin rather than uniparental disomy. Pulsed-field gel electrophoresis has not, so far, revealed any evidence of an altered band pattern; however, studies are continuing. FISH analysis is currently in progress using YACs and cosmids to define the extent of this deletion.

  10. Decoding NF1 Intragenic Copy-Number Variations.

    Science.gov (United States)

    Hsiao, Meng-Chang; Piotrowski, Arkadiusz; Callens, Tom; Fu, Chuanhua; Wimmer, Katharina; Claes, Kathleen B M; Messiaen, Ludwine

    2015-08-06

    Genomic rearrangements can cause both Mendelian and complex disorders. Currently, several major mechanisms causing genomic rearrangements, such as non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), have been proposed. However, to what extent these mechanisms contribute to gene-specific pathogenic copy-number variations (CNVs) remains understudied. Furthermore, few studies have resolved these pathogenic alterations at the nucleotide-level. Accordingly, our aim was to explore which mechanisms contribute to a large, unique set of locus-specific non-recurrent genomic rearrangements causing the genetic neurocutaneous disorder neurofibromatosis type 1 (NF1). Through breakpoint-spanning PCR as well as array comparative genomic hybridization, we have identified the breakpoints in 85 unrelated individuals carrying an NF1 intragenic CNV. Furthermore, we characterized the likely rearrangement mechanisms of these 85 CNVs, along with those of two additional previously published NF1 intragenic CNVs. Unlike the most typical recurrent rearrangements mediated by flanking low-copy repeats (LCRs), NF1 intragenic rearrangements vary in size, location, and rearrangement mechanisms. We propose the DNA-replication-based mechanisms comprising both FoSTeS and/or MMBIR and serial replication stalling to be the predominant mechanisms leading to NF1 intragenic CNVs. In addition to the loop within a 197-bp palindrome located in intron 40, four Alu elements located in introns 1, 2, 3, and 50 were also identified as intragenic-rearrangement hotspots within NF1.

  11. Neurofibromatosis (For Parents)

    Science.gov (United States)

    ... Your Child Natural Disasters: How Families Can Help Neurofibromatosis KidsHealth > For Parents > Neurofibromatosis Print A A A ... Caring for Your Child en español Neurofibromatosis About Neurofibromatosis Neurofibromatosis (NF) is a neurocutaneous syndrome that can ...

  12. Spontaneous remission of primary hyperparathyroidism in a patient with neurofibromatosis type 1: case report

    OpenAIRE

    França, Mariana Martins; Santos, Antonio B. [UNESP; Hirosawa, Renata Midori [UNESP; Tagliarini, José Vicente [UNESP; Mazeto, Gláucia Maria Ferreira da Silva; Nunes, Vania Dos Santos [UNESP

    2012-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder affecting approximately 1 in 3500 individuals. Patients with the disorder can develop carcinoid tumors, medullary thyroid carcinoma, pheochromocytoma and tumor of the hypothalamus. The association of NF1 with Primary Hyperparathyroidism (HPP) is very rare. We report a 56-year-old woman with NF1 who was referred to our service because of nephrolithiasis. Physical examination revealed the characteristic signs of NF1, a...

  13. Ullrich-Turner syndrome and neurofibromatosis-1

    Energy Technology Data Exchange (ETDEWEB)

    Schorry, E.K.; Lovell, A.M.; Saal, H.M. [Children`s Hospital Medical Center, Cincinnati, OH (United States); Milatovich, A. [Stanford Health Services Cytogenetics Lab., CA (United States)

    1996-12-30

    There is a well-known association between neurofibromatosis-1 (NF1) and Noonan syndrome-like manifestations, including short stature, short broad neck, and hypertelorism. These anomalies are thought to be due to variable expression of the NF1 gene. We report on two girls with NF1 who were found to have the Ullrich-Turner syndrome. Case 1, a 12-year-old white girl, was followed in a Neurofibromatosis Clinic because of multiple cafe-au-lait spots and a family history of NF1 in her mother and sister. On examination, she had short stature, hypertelorism, and short neck with low posterior hairline. Karyotype was 86% 46,XY/14% 45,X. Case 2, the first child of a woman with NF1, presented at birth with lymphedema of hands and feet and a short broad neck. Karyotype was 45,X. At age 23 months she was short, had epicanthic folds, hypertelorism, narrow palate, right simian crease, 19 cafe-au-lait spots, and axillary freckling. We conclude that chromosome studies should be performed in girls with NF1 who have short stature and Noonan- or Ullrich-Turner-like findings. Dilemmas raised by the dual diagnoses of NF1 and Ullrich-Turner syndrome include potential risks of growth hormone therapy and estrogen replacement therapy. 14 refs., 2 figs.

  14. Learning Disabilities in Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-12-01

    Full Text Available The frequency of specific leaning disabilities (SLD in neurofibromatosis type 1 (NF1 was determined in a cohort of 81 patients (43 males, 38 females; mean age 11 years 6 months; age range 8-16 followed at Children's Hospital, Westmead, NSW, Australia.

  15. Frequency of Cognitive Deficits in Neurofibromatosis

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-11-01

    Full Text Available The frequency and severity of specific cognitive deficits in 81 children with neurofibromatosis type 1 (NF1, ages 8 to 16 years, compared to 49 unaffected sibling controls, were assessed in a study at the University of Sydney, New South Wales, Australia.

  16. Modeling cognitive dysfunction in neurofibromatosis-1.

    Science.gov (United States)

    Diggs-Andrews, Kelly A; Gutmann, David H

    2013-04-01

    Cognitive dysfunction, including significant impairments in learning, behavior, and attention, is found in over 10% of children in the general population. However, in the common inherited cancer predisposition syndrome, neurofibromatosis type 1 (NF1), the prevalence of these cognitive deficits approaches 70%. As a monogenic disorder, NF1 provides a unique genetic tool to identify and dissect mechanistically the molecular and cellular bases underlying cognitive dysfunction. In this review, we discuss Nf1 fly and mouse systems that mimic many of the cognitive abnormalities seen in children with NF1. Further, we describe discoveries from these models that have uncovered defects in the regulation of Ras activity, cAMP generation, and dopamine homeostasis as key mechanisms important for cognitive dysfunction in children with NF1.

  17. Zebrafish Model of NF1 for Structure-Function Analysis, Mechanisms of Glial Tumorigenesis, and Chemical Biology

    Science.gov (United States)

    2015-08-01

    INTRODUCTION Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 gene. Patients exhibit pigmentation abnormalities...finger cassettes and evaluated their specificity using a bacterial one-hybrid assay. In parallel, we constructed ZFNs from these cassettes and tested their...identification of germline lesions were performed as previously described (Meng et al., 2008; Gupta et al., 2011). Bacterial one-hybrid binding site

  18. Neurofibromatosis Type 1 Presenting with Plexiform Neurofibromas in Two Patients: MRI Features

    Directory of Open Access Journals (Sweden)

    Ahmet Mesrur Halefoglu

    2012-01-01

    Full Text Available Neurofibromatosis type 1 (NF1, also known as peripheral neurofibromatosis or von Recklinghausen’s disease, is one of the most common genetic disorders. It is inherited in an autosomal dominant pattern. Multiple cutaneous neurofibromas are hallmark lesions of NF1. Localized and plexiform neurofibromas of the paraspinal and sacral region are the most common abdominal neoplasms in NF1. Herein, we report two patients with a known history of NF1 presenting with multiple, extensive localized and plexiform neurofibromas. We describe the important distinguishing features of these tumors as seen on magnetic resonance imaging (MRI, including very bright signal intensity and target sign on T2 weighted images.

  19. Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation.

    Science.gov (United States)

    Hirbe, Angela C; Dahiya, Sonika; Friedmann-Morvinski, Dinorah; Verma, Inder M; Clapp, D Wade; Gutmann, David H

    2016-02-16

    Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that arise sporadically or in association with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. In individuals with NF1, MPNSTs are hypothesized to arise from Nf1-deficient Schwann cell precursor cells following the somatic acquisition of secondary cooperating genetic mutations (e.g., p53 loss). To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains. Using this approach, ~60% of mice with Periostin-Cre-mediated Nf1 gene inactivation (Periostin-Cre; Nf1(flox/flox) mice) developed tumors classified as low-grade MPNSTs following p53 knockdown (mean, 6 months). Similarly, ~70% of Nf1+/- mice with GFAP-Cre-mediated Nf1 gene inactivation (GFAP-Cre; Nf1(flox/null) mice) developed low-grade MPNSTs following p53 knockdown (mean, 3 months). In addition, wild-type and Nf1+/- mice with GFAP-Cre-mediated Nf1 loss develop MPNSTs following somatic p53 knockout with different latencies, suggesting potential influences of Nf1+/- stromal cells in MPNST pathogenesis. Collectively, this new MPNST model system permits the analysis of somatically-acquired events as well as tumor microenvironment signals that potentially cooperate with Nf1 loss in the development and progression of this deadly malignancy.

  20. Breast cancer associated with type 1 neurofibromatosis.

    Science.gov (United States)

    Salemis, Nikolaos S; Nakos, Georgios; Sambaziotis, Dimitrios; Gourgiotis, Stavros

    2010-10-01

    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.

  1. Horner syndrome in neurofibromatosis type 1.

    Science.gov (United States)

    Lee, Jang Hyun; Jeen, Yoon-Mi; Kang, Sang Gue; Tark, Min Seung; Kim, Chul Han

    2015-01-01

    The authors report a rare case of Horner syndrome in a patient with neurofibromatosis type 1 (NF-1). A 31-year-old man visited the clinic with drooping left eyelid. The physical examination revealed ptosis of the left eyelid, miotic pupil, facial anhidrosis, and several skin masses on the chest. The radiological examination of the chest demonstrated a well-defined left posterior mediastinal mass close to the vertebral bodies of the upper thoracic spine at the level of T1-T5. The masses of mediastinum and skin were totally removed. They were diagnosed as neurofibromas. Neurofibromatosis type 1 was diagnosed. To the best of my knowledge, this is a rare case of a patient with NF-1 who presented with Horner syndrome. Clinicians should be vigilant on the possibility of Horner syndrome in patients with NF-1.

  2. Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia.

    Science.gov (United States)

    Banerjee, Santasree; Lei, Dongzhu; Liang, Shengran; Yang, Li; Liu, Saijun; Wei, Zhu; Tang, Jian Ping

    2016-12-14

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several café-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several café-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple café-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as "likely pathogenic". Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.

  3. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China.

    Science.gov (United States)

    Zhu, Lude; Zhang, Yunfeng; Tong, Hanxing; Shao, Minhua; Gu, Yong; Du, Xufeng; Wang, Peiru; Shi, Lei; Zhang, Linglin; Bi, Mingye; Wang, Xiuli; Zhang, Guolong

    2016-03-01

    Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene. Detecting mutation in NF1 is hindered by the gene's large size, the lack of mutation hotspots, and the presence of pseudogenes.Our goal was to establish a sensitive, feasible, and comparatively economical protocol to detect NF1 mutations using blood samples.We developed a method to screen patients for mutations. Thirty-two NF1 patients from 32 unrelated families and 120 unrelated population-match controls were investigated in this study. Specific primers were designed for NF1 to avoid pseudogenes. NF1 mutations were detected by sequencing at the deoxyribonucleic acid (DNA) and complementary DNA (cDNA) levels, and multiplex ligation-dependent probe amplification (MLPA) and familial segregation analyses were used.Forty-four specific primers designed according to the NF1 structure were successfully used for polymerase chain reaction (PCR) and DNA sequencing, which was more feasible and useful than cDNA sequencing. Thirty distinct NF1 mutations were identified in 32 patients. Thirteen mutations were novel and most were frameshift mutations (33.3%). Mutations were detected at a rate of 93.8%.Our study suggests that this sensitive, feasible, and comparatively economical protocol is effective for the detection of NF1 mutations.

  4. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.

    Science.gov (United States)

    Ben-Shachar, Shay; Constantini, Shlomi; Hallevi, Hen; Sach, Emma K; Upadhyaya, Meena; Evans, Gareth D; Huson, Susan M

    2013-05-01

    Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P valueNF1 in general (PNF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (PNF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

  5. Pharmacologically targeting beta-catenin for NF1 associated deficiencies in fracture repair.

    Science.gov (United States)

    Baht, Gurpreet S; Nadesan, Puviindran; Silkstone, David; Alman, Benjamin A

    2017-02-22

    Patients with Neurofibromatosis type 1 display delayed fracture healing and the increased deposition of fibrous tissue at the fracture site. Severe cases can lead to non-union and even congenital pseudarthrosis. Neurofibromatosis type 1 is caused by a mutation in the NF1 gene and mice lacking the Nf1 gene show a fracture repair phenotype similar to that seen in patients. Tissue from the fracture site of patients with Neurofibromatosis type 1 and from mice deficient in the Nf1 gene both show elevated levels of β-catenin protein and activation of β-catenin mediated signaling. Constitutively elevated β-catenin leads to a delayed and fibrous fracture repair process, and (RS)-5-methyl-1-phenyl-1,3,4,6-tetrahydro-2,5-benzoxazocine (Nefopam, a centrally-acting, non-narcotic analgesic agent) inhibits β-catenin mediated signaling during skin wound repair. Here we investigate Nefopam's potential as a modulator of bone repair in mice deficient in Nf1. Mice were treated with Nefopam and investigated for bone fracture repair. Bone marrow stromal cells flushed from the long bones of unfractured mice were treated with Nefopam and investigated for osteogenic potential. Treatment with Nefopam was able to lower the β-catenin level and the Axin2 transcript level in the fracture calluses of Nf1 deficient mice. Cultures from the bone marrow of Nf1(-/-) mice had significantly lower osteoblastic colonies and mineralized nodules, which was increased when cells were cultured in the presence of Nefopam. Fracture calluses were harvested and analyzed 14days and 21days after injury. Nf1(-/-) calluses had less bone, less cartilage, and higher fibrous tissue content than control calluses. Treatment with Nefopam increased the bone and cartilage content and decreased the fibrous tissue content in Nf1(-/-) calluses. These findings present a potential treatment for patients with Neurofibromatosis 1 in the context of bone repair. Since Nefopam is already in use in patient care, it could be

  6. Analysis of NFI gene mutations detected by Ion Torrent sequencing technology in patients with neurofibromatosis type Ⅰ%Ion Torrent测序技术检测Ⅰ型神经纤维瘤病患者NF1基因突变

    Institute of Scientific and Technical Information of China (English)

    朱艳慧; 胡朝晖; 毕欣; 喻长顺; 许若思; 王晓春

    2013-01-01

    目的 评价Ion Torrent测序技术检测Ⅰ型神经纤维瘤(NF1)基因及其突变类型的可行性.方法 提取12例NF1患者的外周血DNA,用Ion Torrent个体化基因测序仪(PGM)对患者NF1基因进行测序,用Sanger测序法验证NF1基因相应的突变位点,Ion Torrent PGM检测后覆盖缺失的外显子样本用Sanger测序法重新检测.结果 检测到10例患者存在NF1基因致病突变,其中2种无义突变,5种小缺失或插入突变,1种错义突变,2种剪接突变.2例患者未检测到致病突变.结论 Ion Torrent测序技术检测舍有大量外显子的NF1基因快速、准确;NF1基因突变可导致氨基酸密码子提前终止.

  7. Incidental (malignancy) and coincidental (idiopathic polydactylous longitudinal erythronychia) conditions in patients with segmental neurofibromatosis.

    Science.gov (United States)

    Cohen, Philip R

    2013-04-01

    Segmental neurofibromatosis (SNF) is an uncommon presentation of neurofibromatosis type 1 (NF-1). Although patients with SNF are at a lower risk for developing NF-l-associated complications, the estimated occurrence of related malignancies may be approaching the frequency observed in patients with NF-1. Idiopathic polydactylous longitudinal erythronychia also may be associated with SNF, though the frequency of this association remains to be determined.

  8. Pharmacological inhibition of Anaplastic Lymphoma Kinase rescues spatial memory impairments in Neurofibromatosis 1 mutant mice.

    Science.gov (United States)

    Weiss, Joseph B; Weber, Sydney; Marzulla, Tessa; Raber, Jacob

    2017-08-14

    Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Loss of NF1 expression in human endothelial cells promotes autonomous proliferation and altered vascular morphogenesis.

    Directory of Open Access Journals (Sweden)

    Anshika Bajaj

    Full Text Available Neurofibromatosis is a well known familial tumor syndrome, however these patients also suffer from a number of vascular anomalies. The loss of NFl from the endothelium is embryonically lethal in mouse developmental models, however little is known regarding the molecular regulation by NF1 in endothelium. We investigated the consequences of losing NF1 expression on the function of endothelial cells using shRNA. The loss of NF1 was sufficient to elevate levels of active Ras under non-stimulated conditions. These elevations in Ras activity were associated with activation of downstream signaling including activation of ERK, AKT and mTOR. Cells knocked down in NF1 expression exhibited no cellular senescence. Rather, they demonstrated augmented proliferation and autonomous entry into the cell cycle. These proliferative changes were accompanied by enhanced expression of cyclin D, phosphorylation of p27(KIP, and decreases in total p27(KIP levels, even under growth factor free conditions. In addition, NF1-deficient cells failed to undergo normal branching morphogenesis in a co-culture assay, instead forming planar islands with few tubules and branches. We find the changes induced by the loss of NF1 could be mitigated by co-expression of the GAP-related domain of NF1 implicating Ras regulation in these effects. Using doxycycline-inducible shRNA, targeting NF1, we find that the morphogenic changes are reversible. Similarly, in fully differentiated and stable vascular-like structures, the silencing of NF1 results in the appearance of abnormal vascular structures. Finally, the proliferative changes and the abnormal vascular morphogenesis are normalized by low-dose rapamycin treatment. These data provide a detailed analysis of the molecular and functional consequences of NF1 loss in human endothelial cells. These insights may provide new approaches to therapeutically addressing vascular abnormalities in these patients while underscoring a critical role for

  10. Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation.

    Science.gov (United States)

    Stansfield, Brian K; Bessler, Waylan K; Mali, Raghuveer; Mund, Julie A; Downing, Brandon D; Kapur, Reuben; Ingram, David A

    2014-01-01

    Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1(+/-)) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury. However, the downstream Ras effector pathway responsible for this phenotype is unknown. Based on in vitro assays demonstrating enhanced extracellular signal-related kinase (Erk) signaling in Nf1(+/-) macrophages and vascular smooth muscle cells and in vivo evidence of Erk amplification without alteration of phosphatidylinositol 3-kinase signaling in Nf1(+/-) neointimas, we tested the hypothesis that Ras-Erk signaling regulates intimal proliferation in a murine model of NF1 arterial stenosis. By using a well-established in vivo model of inflammatory cell migration and standard cell culture, neurofibromin-deficient macrophages demonstrate enhanced sensitivity to growth factor stimulation in vivo and in vitro, which is significantly diminished in the presence of PD0325901, a specific inhibitor of Ras-Erk signaling in phase 2 clinical trials for cancer. After carotid artery injury, Nf1(+/-) mice demonstrated increased intimal proliferation compared with wild-type mice. Daily administration of PD0325901 significantly reduced Nf1(+/-) neointima formation to levels of wild-type mice. These studies identify the Ras-Erk pathway in neurofibromin-deficient macrophages as the aberrant pathway responsible for enhanced neointima formation.

  11. Neurofibromatosis Specialists

    Science.gov (United States)

    ... Los Angeles, CA Children’s Hospital of Orange County CHOC Neurofibromatosis Clinic • Orange, CA Lucile Packard Children’s Hospital, ... Los Angeles, CA Children’s Hospital of Orange County CHOC Neurofibromatosis Clinic • Orange, CA Children’s National Health System ...

  12. Gene expression profiling of cultured human NF1 heterozygous (NF1+/-) melanocytes reveals downregulation of a transcriptional cis-regulatory network mediating activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.

    Science.gov (United States)

    Boucneau, Joachim; De Schepper, Sofie; Vuylsteke, Marnik; Van Hummelen, Paul; Naeyaert, Jean-Marie; Lambert, Jo

    2005-08-01

    One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where disregulation of melanocyte biology is supposed to play a key etiopathogenic role. To gain better insight into the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented skin and hyperpigmented lesional café-au-lait skin. From the magnitude of gene effects, we found that gene expression was affected most strongly by genotype and less so by lesional type. A total of 137 genes had a significant twofold or more up- (72) or downregulated (65) expression in NF1+/- melanocytes compared with NF1+/+ melanocytes. Melanocytes cultured from hyperpigmented café-au-lait skin showed 37 upregulated genes whereas only 14 were downregulated compared with normal skin melanocytes. In addition, significant genotype xlesional type interactions were observed for 465 genes. Differentially expressed genes were mainly involved in regulating cell proliferation and cell adhesion. A high number of transcription factor genes, among which a specific subset important in melanocyte lineage development, were downregulated in the cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene. Although the results presented have been obtained with a restricted number of patients (one NF1 patient and one control) and using cDNA microarrays that may limit their interpretation, the data nevertheless addresses for the first time the effect of a heterozygous NF1 gene on the expression of the human melanocyte transcriptome and has generated several interesting candidate genes helpful in elucidating the etiopathology of café-au-lait macules in NF1 patients.

  13. Pheochromocytoma in neurofibromatosis type 1 during pregnancy.

    Science.gov (United States)

    Remón-Ruiz, Pablo; Aliaga-Verdugo, Alberto; Guerrero-Vázquez, Raquel

    2017-02-01

    Pregnant women with neurofibromatosis type 1 (NF-1) have increased complications during gestation, including hypertensive disorders that are sometimes caused by pheochromocytoma. Pheochromocytoma is an extremely rare condition during pregnancy, and the main clinical manifestation is hypertension. If not properly treated, pheochromocytoma has high maternal and fetal mortality rates. Early recognition and adequate clinical management before delivery have led to better outcomes in the last few decades. Despite the association of NF-1 and pheochromocytoma, there are few clinical reports of these two conditions in pregnant patients. We present a rare case of pheochromocytoma diagnosed during pregnancy in a patient with NF-1, and we describe the treatment and the obstetric and fetal outcomes. We also review other medical conditions related to NF-1 that complicated this patient's pregnancy.

  14. SEGMENTAL NEUROFIBROMATOSIS: A REPORT OF 3 CASES

    Science.gov (United States)

    Gabhane, Sushma Kashinath; Kotwal, Mrunmayi Nishikant; Bobhate, Sudhakar K

    2010-01-01

    Neurofibromatosis is a genetic disorder of neural crest-derived cells that primarily affect growth of neural tissues. It is broadly divided into three categories: (a) von Recklinghausen's neurofibromatosis or NF-1, (b) bilateral acoustic neuroma (NF-2), and (c) all other neurofibromatoses, including alternate or atypical forms of the disease. The patients with generalized form of NF1 are characterized by multiple café-au-lait spots and neurofibromas and diagnosed easily. But when an individual has small number of lesions in a limited region of the body it could be neglected by the patient or not be recognized by the clinicians as a segmental form of neurofibromatosis. We describe three cases of segmental neurofibromatosis (SNF). These cases have been classified as segmental NF according to Riccardi's definition of SNF and classification of neurofibromatosis. Segmental form of NF may evolve into a complete form over time. Also, this disorder may be transmitted to the offspring's of these individuals. Hence genetic counseling of these individuals must include these facts. PMID:20418991

  15. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells.

    Science.gov (United States)

    Zhou, Yuan; He, Yongzheng; Sharma, Richa; Xing, Wen; Estwick, Selina A; Wu, Xiaohua; Rhodes, Steven D; Xu, Mingjiang; Yang, Feng-Chun

    2015-06-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1(+/-)) mice. Nf1(+/-) MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1(+/-) MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1(+/-) MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.

  16. Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Yuan Zhou

    2015-06-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1+/− mice. Nf1+/− MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT MSPCs. Additionally, Nf1+/− MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1+/− MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K and mitogen activated protein kinase (MAPK signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.

  17. Dystrophic spinal deformities in a neurofibromatosis type 1 murine model.

    Directory of Open Access Journals (Sweden)

    Steven D Rhodes

    Full Text Available Despite the high prevalence and significant morbidity of spinal anomalies in neurofibromatosis type 1 (NF1, the pathogenesis of these defects remains largely unknown. Here, we present two murine models: Nf1flox/-;PeriCre and Nf1flox/-;Col.2.3Cre mice, which recapitulate spinal deformities seen in the human disease. Dynamic histomorphometry and microtomographic studies show recalcitrant bone remodeling and distorted bone microarchitecture within the vertebral spine of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice, with analogous histological features present in a human patient with dystrophic scoliosis. Intriguingly, 36-60% of Nf1flox/-;PeriCre and Nf1flox/-;Col2.3Cre mice exhibit segmental vertebral fusion anomalies with boney obliteration of the intervertebral disc (IVD. While analogous findings have not yet been reported in the NF1 patient population, we herein present two case reports of IVD defects and interarticular vertebral fusion in patients with NF1. Collectively, these data provide novel insights regarding the pathophysiology of dystrophic spinal anomalies in NF1, and provide impetus for future radiographic analyses of larger patient cohorts to determine whether IVD and vertebral fusion defects may have been previously overlooked or underreported in the NF1 patient population.

  18. Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis.

    NARCIS (Netherlands)

    Doorn, P F; Molenaar, W M; Buter, J; Hoekstra, H J

    1995-01-01

    Malignant peripheral nerve sheath tumors (MPNST) are rare. They account for 10% of all soft tissue sarcomas. The incidence of MPNST in patients with neurofibromatosis type 1 (NF-1) is 4%. A retrospective study was undertaken to evaluate the prognosis of patients with MPNST and NF-1 vs patients with

  19. Plexiform neurofibroma of the eye region occurring in patients without neurofibromatosis type 1

    DEFF Research Database (Denmark)

    Bechtold, Dorte; Hove, Hanne D; Prause, Jan Ulrik

    2012-01-01

    The purpose of the present study was to investigate the correlation between Plexiform Neurofibroma (PN) of the eye region and Neurofibromatosis type 1 (NF1). According to the textbooks of ophthalmology, PN and NF1 are very closely linked. Our clinical experience raised doubts about this, however....

  20. HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1

    NARCIS (Netherlands)

    Omrani, A; van der Vaart, T; Mientjes, E; van Woerden, G M; Hojjati, M R; Li, K W; Gutmann, D H; Levelt, C N; Smit, A B; Silva, A J; Kushner, S A; Elgersma, Y

    2015-01-01

    Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity h

  1. Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein.

    NARCIS (Netherlands)

    Yang, G.; Khalaf, W.; Locht, L.; Jansen, J.H.; Gao, M.; Thompson, M.A.; Reijden, B.A. van der; Gutmann, D.H.; Delwel, R.; Clapp, D.W.; Hiebert, S.W.

    2005-01-01

    Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are no

  2. Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

    NARCIS (Netherlands)

    Chabernaud, C.; Mennes, M.J.J.; Kardel, P.G.; Gaillard, W.D.; Kalbfleisch, M.L.; Vanmeter, J.W.; Packer, R.J.; Milham, M.P.; Castellanos, F.X.; Acosta, M.T.

    2012-01-01

    In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a Phase 1 open-label trial was to examine th

  3. Does Attention-Deficit-Hyperactivity Disorder Exacerbate Executive Dysfunction in Children with Neurofibromatosis Type 1?

    Science.gov (United States)

    Payne, Jonathan M.; Arnold, Shelley S.; Pride, Natalie A.; North, Kathryn N.

    2012-01-01

    Aim: Although approximately 40% of children with neurofibromatosis type 1 (NF1) meet diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD), the impact of ADHD on the executive functioning of children with NF1 is not understood. We investigated whether spatial working memory and response inhibition are impaired in children with…

  4. HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1

    NARCIS (Netherlands)

    Omrani, A; van der Vaart, T; Mientjes, E; van Woerden, G M; Hojjati, M R; Li, K W; Gutmann, D H; Levelt, C N; Smit, A B; Silva, A J; Kushner, S A; Elgersma, Y

    2015-01-01

    Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity

  5. Functional analysis of splicing mutations in exon 7 of NF1 gene

    Directory of Open Access Journals (Sweden)

    Calvieri Stefano

    2007-02-01

    Full Text Available Abstract Background Neurofibromatosis type 1 is one of the most common autosomal dominant disorders, affecting about 1:3,500 individuals. NF1 exon 7 displays weakly defined exon-intron boundaries, and is particularly prone to missplicing. Methods In this study we investigated the expression of exon 7 transcripts using bioinformatic identification of splicing regulatory sequences, and functional minigene analysis of four sequence changes [c.910C>T (R304X, c.945G>A/c.946C>A (Q315Q/L316M, c.1005T>C (N335N] identified in exon 7 of three different NF1 patients. Results Our results detected the presence of three exonic splicing enhancers (ESEs and one putative exonic splicing silencer (ESS element. The wild type minigene assay resulted in three alternative isoforms, including a transcript lacking NF1 exon 7 (NF1ΔE7. Both the wild type and the mutated constructs shared NF1ΔE7 in addition to the complete messenger, but displayed a different ratio between the two transcripts. In the presence of R304X and Q315Q/L316M mutations, the relative proportion between the different isoforms is shifted toward the expression of NF1ΔE7, while in the presence of N335N variant, the NF1ΔE7 expression is abolished. Conclusion In conclusion, it appears mandatory to investigate the role of each nucleotide change within the NF1 coding sequence, since a significant proportion of NF1 exon 7 mutations affects pre-mRNA splicing, by disrupting exonic splicing motifs and modifying the delicate balance between aberrantly and correctly spliced transcripts.

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

    Science.gov (United States)

    Mavani, Gaurang; Kesar, Vivek; Devita, Maria V.; Rosenstock, Jordan L.; Michelis, Michael F.; Schwimmer, Joshua A.

    2014-01-01

    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. PMID:25852916

  7. Laryngeal Manifestations of Neurofibromatosis.

    Science.gov (United States)

    Naunheim, Matthew R; Plotkin, Scott R; Franco, Ramon A; Song, Phillip C

    2016-03-01

    To describe the range of findings in patients with neurofibromatosis (NF) presenting to a laryngology clinic and to analyze the etiologic factors of vocal fold dysfunction in this cohort. Case series with chart review. Tertiary laryngology practice. All cases of NF presenting to an academic laryngology practice were retrospectively reviewed (August 2005 to May 2014), with a total of 34 cases. Demographic data, symptoms, and endoscopic examination findings were reviewed. Etiologic factors of laryngeal complaints were analyzed with reference to NF-associated pathologies and surgical history. Thirty-four patients with NF-1 or NF-2 were evaluated, and 28 of these patients (6 NF-1 and 22 NF-2) had laryngeal pathology. The most common presenting symptoms were vocal weakness (n = 21), dysphagia (n = 5), and globus (n = 4). Three patients had NF-related vocal fold masses on examination, including 2 neurofibromas and 1 schwannoma. Unilateral vocal cord paralysis was seen in 17 patients; bilateral paralysis was observed in 5 patients. Of patients with unilateral or bilateral paralysis, 20 had intracranial masses (vestibular schwannoma, meningioma, or skull base tumors), and 16 had previously undergone surgery for these lesions. Of the patients with NF-associated intracranial tumors, 87.0% presented with vocal cord paralysis, whereas only 40.0% of those without intracranial masses had paralysis (P = .0560). Seven patients underwent medialization procedures. Neurofibromatosis patients may present to laryngology clinic with primary laryngeal tumors or, more commonly, unilateral or bilateral paralysis. Otolaryngologists should be keenly aware of vocal fold paralysis caused by the NF-associated tumors, with particular attention to bilateral paralysis in NF-2. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

  8. Lower fasting blood glucose in neurofibromatosis type 1

    Science.gov (United States)

    Martins, Aline Stangherlin; Jansen, Ann Kristine; Rodrigues, Luiz Oswaldo Carneiro; Matos, Camila Maria; Souza, Marcio Leandro Ribeiro; de Souza, Juliana Ferreira; Diniz, Maria de Fátima Haueisen Sander; Barreto, Sandhi Maria; Diniz, Leonardo Mauricio; de Rezende, Nilton Alves; Riccardi, Vincent Michael

    2015-01-01

    Studies indicate a lower occurrence of diabetes mellitus (DM) in patients with neurofibromatosis type 1 (NF1). Fasting blood glucose (FBG) level is the main criterion used to diagnose DM and glucose intolerance. Therefore, this study compared FBG level between adults with NF1 and non-NF1 controls. We selected clinical records of 57 out of 701 individuals attending the Neurofibromatosis Outpatient Reference Center of the Clinics Hospital of the Federal University of Minas Gerais in Brazil. The selected patients with NF1 were matched to non-NF1 controls selected from the Brazilian Longitudinal Study of Adult Health according to sex, age (range, 35–74 years) and BMI at a ratio of 1:3. In both groups, individuals with DM were excluded. Median FBG level in the NF1 group (86 mg/dl (range, 56–127 mg/dl)) was lower than that in the non-NF1 control group (102 mg/dl (range, 85–146 mg/dl)) (P<0.001). Prevalence of FBG level ≥100 mg/dl in the NF1 group (16%) was lower than that in the non-NF1 control group (63%) (P<0.05). The chance of a high FBG level was 89% lower in the NF1 group (odds ratio, 0.112; 95% CI, 0.067–0.188) (P<0.05). In conclusion, adults with NF1 showed a lower FBG level and a lower prevalence of high FBG level compared with non-NF1 controls. PMID:26631381

  9. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends

    OpenAIRE

    Vogiaki Sophia; Korkolis Dimitris; Aggeli Chrysanthi; Zagouri Flora; Vasiliadis George K; Zografos George N; Pagoni Matina K; Kaltsas Gregory; Piaditis George

    2010-01-01

    Abstract Background Neurofibromatosis Type 1(NF-1) has autosomal dominant inheritance with complete penetrance, variable expression and a high rate of new mutation. Pheochromocytoma occurs in 0.1%-5.7% of patients with NF-1. Case presentation We present the case of a 37-year-old patient with laparoscopically resected pheochromocytoma. He was investigated for hypertension, flushing and ectopic heart beat. Abdominal CT and MRI revealed a mass measuring 8 × 4 cm in the right adrenal gland. The d...

  10. Cerebral multicystic lesions in a child with neurofibromatosis

    OpenAIRE

    İsikay, Sedat; Yilmaz, Kutluhan

    2013-01-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominant neurocutaneous syndrome, with frequent involvement of the central nervous system (CNS). As well as abnormal cellular differentiation, disordered cell migration during development is the most common cause of the various brain lesions. Cystic lesions are rarely observed in neurocutaneous diseases, and the origin of the cysts is not known. This paper presents a rare case, a child at the age of 3, who was diagnosed as NF-1 and was observed ...

  11. Atypical meningioma and extensive calvarium defects in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Simsek, Enver [Department of Paediatrics, Duzce Medical Faculty, Abant Izzet Baysal University, Konuralp-Duzce (Turkey); Yavuz, Cevdet [Department of Neurosurgery, Duzce Medical Faculty, Abant Izzet Baysal University, Konuralp-Duzce (Turkey); Ustundag, Nil [Department of Pathology, Abant Izzet Baysal University School of Medicine, Konuralp-Duzce (Turkey)

    2003-08-01

    A 9-year-old girl with neurofibromatosis type 1 (NF1) presented with a massive atypical meningioma and calvarial defect. Skull radiographs and cranial CT showed an extensive lytic bone lesion at the vertex. MRI demonstrated a large mass invading the calvarium and sagittal sinus. The histopathological and immunohistochemical diagnosis of the resected mass was atypical meningioma. To our knowledge, this is the first case of NF1 associated with atypical meningioma and massive calvarial defect in a child. (orig.)

  12. [Segmental neurofibromatosis].

    Science.gov (United States)

    Zulaica, A; Peteiro, C; Pereiro, M; Pereiro Ferreiros, M; Quintas, C; Toribio, J

    1989-01-01

    Four cases of segmental neurofibromatosis (SNF) are reported. It is a rare entity considered to be a localized variant of neurofibromatosis (NF)-Riccardi's type V. Two cases are male and two female. The lesions are located to the head in a patient and the other three cases in the trunk. No family history nor transmission to progeny were manifested. The rest of the organs are undamaged.

  13. [Seizures in neurofibromatosis. What is the risk?].

    Science.gov (United States)

    Drouet, A

    2011-12-01

    The prevalence and the type of seizures associated with neurofibromatosis 1 (NF1) and 2 (NF2) are not adequately characterized. NF1 has a birth incidence of one in 2500, and NF2 one in 25000. Seizures are an occasional complication in NF1 patients and there is no data for NF2 patients. Central nervous system tumors are always suspected, since NF1 and NF2 are caused by mutations in tumor suppressor gene controlling cell proliferation and differentiation. The aim of this article is to provide a synthetic overview about epilepsy associated with NF1 and NF2 based on published studies. In NF1, the type of seizures and their response to therapy are reported, the heterogeneity of etiology is also discussed. For NF2 patients, no specific data are available; the current knowledge comes from series of NF2 patients for which seizures has revealed the disease or from isolated case reports of tumors associated with seizures. Cryptogenic epilepsy without anatomic defect is likely to be related to NF1, while seizures seem to be secondary to leptomeningeal tumors (meningioma, meningioangiomatosis) in NF2 patients. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  14. Neurofibromatosis type 1 and autoimmune hyperthyroidism in a 10,5 years-old girl

    Directory of Open Access Journals (Sweden)

    Huseyin Demirbilek

    2013-08-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant inherited multisystem disease associated with several endocrine disorders. Association of NF1 and hyperthyroidism is extremely rare. All previously reported cases were in adult age group. Herein, we present autoimmune thyrotoxicosis associated to NF1 in a pediatric patient presenting with goiter and symptoms of thyrotoxicosis. [Cukurova Med J 2013; 38(4.000: 805-808

  15. Chronic myeloid leukemia in an adult ghanaian with sporadic neurofibromatosis 1

    Directory of Open Access Journals (Sweden)

    Edeghonghon E Olayemi

    2011-01-01

    Full Text Available Patients with neurofibromatosis type 1 (NF1, a common, progressive, autosomal dominant neurocutaneous disorder, are predisposed to malignancies. Several types of hematologic malignancies have been described in them. However, to date there has been no report to the best of our knowledge of a patient with NF1 developing chronic myeloid leukemia (CML. We present an adult Ghanaian with NF1, who subsequently developed CML. Relevance of the case report is discussed.

  16. Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1.

    Science.gov (United States)

    Strowd, Roy E; Rodriguez, Fausto J; McLendon, Roger E; Vredenburgh, James J; Chance, Aaron B; Jallo, George; Olivi, Alessandro; Ahn, Edward S; Blakeley, Jaishri O

    2016-06-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.

  17. Unilateral absence of sphenoid wing in a Neurofibromatosis type 1 patient: imaging findings

    Directory of Open Access Journals (Sweden)

    Emine Dağıstan

    2013-09-01

    Full Text Available Neurofibromatosis type 1(NF-1 or von Recklinghausendisease is the most common of the neurocutaneous syndromes.It is characterized by pigmented cutaneous lesionsand tumors of central nervous system. By the way,it could affect all the systems of the body. Sphenoid wingabnormalities are very rare and often associated withNF-1 so, they are considered pathognomonic. We reportan unusual case NF-1 with unilateral absence of sphenoidwing and findings of multi-detector computed tomographyand magnetic resonance imaging. J Clin Exp Invest2013; 4 (3: 364-366Key words: Neurofibromatosis type 1, multi-detector computed tomography, magnetic resonance imaging,sphenoid dysplasia.

  18. Neurofibromatosis: part 2 – clinical management

    Directory of Open Access Journals (Sweden)

    Pollyanna Barros Batista

    2015-06-01

    Full Text Available Part 1 of this guideline addressed the differential diagnosis of the neurofibromatoses (NF: neurofibromatosis type 1 (NF1, neurofibromatosis type 2 (NF2 and schwannomatosis (SCH. NF shares some features such as the genetic origin of the neural tumors and cutaneous manifestations, and affects nearly 80 thousand Brazilians. Increasing scientific knowledge on NF has allowed better clinical management and reduced rate of complications and morbidity, resulting in higher quality of life for NF patients. Most medical doctors are able to perform NF diagnosis, but the wide range of clinical manifestations and the inability to predict the onset or severity of new features, consequences, or complications make NF management a real clinical challenge, requiring the support of different specialists for proper treatment and genetic counseling, especially in NF2 and SCH. The present text suggests guidelines for the clinical management of NF, with emphasis on NF1.

  19. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.

    Science.gov (United States)

    Ekvall, Sara; Sjörs, Kerstin; Jonzon, Anders; Vihinen, Mauno; Annerén, Göran; Bondeson, Marie-Louise

    2014-03-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present. © 2013 Wiley Periodicals, Inc.

  20. Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology.

    Science.gov (United States)

    Toonen, Joseph A; Solga, Anne C; Ma, Yu; Gutmann, David H

    2017-01-01

    Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice. We demonstrate that female Nf1-OPG mice exhibit greater retinal ganglion cell (RGC) loss and only females have retinal nerve fiber layer (RNFL) thinning, despite mice of both sexes harboring tumors of identical volumes and proliferation. Female gonadal sex hormones are responsible for this sexual dimorphism, as ovariectomy, but not castration, of Nf1-OPG mice normalizes RGC survival and RNFL thickness. In addition, female Nf1-OPG mice have threefold more microglia than their male counterparts, and minocycline inhibition of microglia corrects the retinal pathology. Moreover, pharmacologic inhibition of microglial estrogen receptor-β (ERβ) function corrects the retinal abnormalities in female Nf1-OPG mice. Collectively, these studies establish that female gonadal sex hormones underlie the sexual dimorphic differences in Nf1 optic glioma-induced retinal dysfunction by operating at the level of tumor-associated microglial activation.

  1. Choroidal Freckling in Pediatric Patients Affected by Neurofibromatosis Type 1.

    Science.gov (United States)

    Vagge, Aldo; Nelson, Leonard B; Capris, Paolo; Traverso, Carlo Enrico

    2016-09-01

    Greater understanding of choroidal freckling in patients affected by neurofibromatosis type 1 (NF1) has changed the previous belief that choroidal lesions are unusual in eyes with this disease. In fact, the high frequency of freckling suggests that the choroid is a structure commonly affected in patients with NF1. A review of patients aged 16 years or younger was performed. Recent studies using near-infrared reflectance imaging have shown that choroidal freckling frequently occurred in pediatric patients. As a result of these findings, some authors have suggested that choroidal freckling should be considered as a new diagnostic criterion for NF1. [J Pediatr Ophthalmol Strabismus. 2016;53(5):271-274.].

  2. Feocromocitoma asociado a neurofibromatosis de von Recklinghausen Pheochromocytoma associated with von Recklinghausen neurofibromatosis

    Directory of Open Access Journals (Sweden)

    Ramón N. Herrera

    2007-10-01

    Full Text Available El feocromocitoma es un tumor glandular adrenal secretor de hormonas epinefrina y norepinefrina, responsables de regular la frecuencia cardíaca y la presión arterial, entre otras funciones. Este tumor puede ocurrir solo o en combinación con otros desórdenes; los factores genéticos y ambientales juegan un rol clave en su aparición. La neurofibromatosis tipo 1 (NF-1 es un desorden genético frecuente que se hereda en forma autosómica dominante, caracterizado por la formación de neurofibromas (tumores que involucran los nervios tisulares en piel, tejido subcutáneo, nervios craneales y espinales. La NF-1 se diagnostica generalmente con el examen físico. No existe un tratamiento curativo para la NF-1, pero hay modos de tratar algunas de sus complicaciones. La hipertensión arterial en la neurofibromatosis causada por un feocromocitoma es extremadamente rara con una incidencia de menos del 1% en menores de 10 años y en adultos jóvenes. Presentamos el caso clínico de una mujer joven con hipertensión de reciente diagnóstico, con la infrecuente asociación de neurofibromatosis y feocromocitoma. Discutimos los mecanismos fisiopatológicos subyacentes y sus implicancias clínicas.A pheochromo cytoma is an adrenal gland tumor that secretes epinephrine and norepinephrine hormones, and is responsible for regulating heart rate and blood pressure, among other functions. The condition can occur alone or in combination with other disorders, and genetic and environmental factors play a key role. Neurofibromatosis- 1 (NF-1 an inherited "autosomal dominant" disorder is one of the most common genetic disorders, characterized by formation of neurofibromas (tumors involving nerve tissue in the skin, subcutaneous tissue, cranial and spinal root nerves. NF1 generally is diagnosed by physical examination. There is no cure for NF1, but there are ways to treat some of its effects. Neurofibromatosis arterial hypertension caused by pheochromocytoma is extremely

  3. Young Australian adults with NF1 have poor access to health care, high complication rates, and limited disease knowledge.

    Science.gov (United States)

    Oates, Emily C; Payne, Jonathan M; Foster, Sheryl L; Clarke, Nigel F; North, Kathryn N

    2013-04-01

    Neurofibromatosis type 1 (NF1) is a multisystem disease associated with a lifelong risk of debilitating and potentially life-limiting complications, however many adults with NF1 have no regular health surveillance. We interviewed and examined 17 young adults with NF1 between the ages of 25 and 33. Most had not been assessed for NF1-related complications within the previous 8 years, including patients with known serious vascular complications, for example, renal artery stenosis. Acute and/or chronic pain, particularly back and plexiform-related pain were common symptoms, and despite a significant impact on quality of life, was untreated in most instances. Symptom and examination-directed imaging revealed serious complications in 41% of the cohort. These included severe spinal cord compression (two cases), a highly SUV avid lesion suggestive of malignancy (one case), and a Juvenile Pilocytic Astrocytoma in a patient without any previous NF1-related complications. Few study participants had a good understanding of NF1, its associated risks and complications, and many had not sought appropriate medical advice as questions or problems arose. NF1-related cognitive deficits in some participants, and the lack of a clear source of expert medical advice for adults with NF1 likely contributed to poor health surveillance and management in this population. Overall, these findings suggest that many Australian adults with NF1 are at risk of serious and life-threatening medical complications, but are not accessing and receiving adequate health care. Access to multidisciplinary adult clinics that specialize in NF1 may address many of the unmet health needs of young adults with NF1.

  4. Neurofibromatosis type 1 and multiple sclerosis: Genetically related ...

    African Journals Online (AJOL)

    Solaf M. Elsayed

    2016-10-25

    Oct 25, 2016 ... Abstract Neurofibromatosis type I (NF1) is an autosomal dominant disorder with involvement of ... sense of pins and needles in lower limbs up to her knees. It .... relapsing MS which is also progressive in nature from the start.

  5. Immunohistochemical NF1 analysis does not predict NF1 gene mutation status in pheochromocytoma.

    Science.gov (United States)

    Stenman, Adam; Svahn, Fredrika; Welander, Jenny; Gustavson, Boel; Söderkvist, Peter; Gimm, Oliver; Juhlin, C Christofer

    2015-03-01

    Pheochromocytomas (PCCs) are tumors originating from the adrenal medulla displaying a diverse genetic background. While most PCCs are sporadic, about 40 % of the tumors have been associated with constitutional mutations in one of at least 14 known susceptibility genes. As 25 % of sporadic PCCs harbor somatic neurofibromin 1 gene (NF1) mutations, NF1 has been established as the most recurrently mutated gene in PCCs. To be able to pinpoint NF1-related pheochromocytoma (PCC) disease in clinical practice could facilitate the detection of familial cases, but the large size of the NF1 gene makes standard DNA sequencing methods cumbersome. The aim of this study was to examine whether mutations in the NF1 gene could be predicted by immunohistochemistry as a method to identify cases for further genetic characterization. Sixty-seven PCCs obtained from 67 unselected patients for which the somatic and constitutional mutational status of NF1 was known (49 NF1 wild type, 18 NF1 mutated) were investigated for NF1 protein immunoreactivity, and the results were correlated to clinical and genetic data. NF1 immunoreactivity was absent in the majority of the PCCs (44/67; 66 %), including 13 out of 18 cases (72 %) with a somatic or constitutional NF1 mutation. However, only a minority of the NF1 wild-type PCCs (18/49; 37 %) displayed retained NF1 immunoreactivity, thereby diminishing the specificity of the method. We conclude that NF1 immunohistochemistry alone is not a sufficient method to distinguish between NF1-mutated and non-mutated PCCs. In the clinical context, genetic screening therefore remains the most reliable tool to detect NF1-mutated PCCs.

  6. Autonomic thermoregulatory dysfunction in neurofibromatosis type 1

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    Luciana G Madeira

    Full Text Available ABSTRACT Objective Neurofibromatosis type 1 (NF1 causes neural and cutaneous disorders and reduced exercise capacity. Exercise/heat exposure increasing internal temperature must be compensated by eccrine sweat function and warmed skin vasodilation. We suspected NF1 could adversely affect eccrine sweat function and/or vascular thermoregulatory responses (VTR. Methods The eccrine sweat function and VTR of 25 NF1 volunteers (14 males, 11 females; 16–57 years old were compared with 23 non-NF1 controls matched by sex, age, height and weight (CG. Sweating was induced by 1 pilocarpine 1% iontophoresis (PILO; and 2 by passive heating (HEAT via the lower third of the legs being immersed in 42°C water for one hour. Previously established eccrine sweat function and VTR protocols were used. Results The NF1 group showed: a lower sweat rate than the CG group during PILO; b a smaller diastolic pressure decrease; and c higher tympanic temperatures than controls during HEAT (p < 0.05. Conclusion Reduced sweating and vascular thermoregulatory responses suggest autonomic dysfunction in NF1 individuals.

  7. Neurofibromin deficiency-associated transcriptional dysregulation suggests a novel therapy for tibial pseudoarthrosis in NF1.

    Science.gov (United States)

    Paria, Nandina; Cho, Tae-Joon; Choi, In Ho; Kamiya, Nobuhiro; Kayembe, Kay; Mao, Rong; Margraf, Rebecca L; Obermosser, Gerlinde; Oxendine, Ila; Sant, David W; Song, Mi Hyun; Stevenson, David A; Viskochil, David H; Wise, Carol A; Kim, Harry K W; Rios, Jonathan J

    2014-12-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in NF1. Among the earliest manifestations is tibial pseudoarthrosis and persistent nonunion after fracture. To further understand the pathogenesis of pseudoarthrosis and the underlying bone remodeling defect, pseudoarthrosis tissue and cells cultured from surgically resected pseudoarthrosis tissue from NF1 individuals were analyzed using whole-exome and whole-transcriptome sequencing as well as genomewide microarray analysis. Genomewide analysis identified multiple genetic mechanisms resulting in somatic biallelic NF1 inactivation; no other genes with recurring somatic mutations were identified. Gene expression profiling identified dysregulated pathways associated with neurofibromin deficiency, including phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways. Unlike aggressive NF1-associated malignancies, tibial pseudoarthrosis tissue does not harbor a high frequency of somatic mutations in oncogenes or other tumor-suppressor genes, such as p53. However, gene expression profiling indicates that pseudoarthrosis tissue has a tumor-promoting transcriptional pattern, despite lacking tumorigenic somatic mutations. Significant overexpression of specific cancer-associated genes in pseudoarthrosis highlights a potential for receptor tyrosine kinase inhibitors to target neurofibromin-deficient pseudoarthrosis and promote proper bone remodeling and fracture healing.

  8. Goblet Cell Carcinoid in a Patient with Neurofibromatosis Type 1: A Rare Combination

    Directory of Open Access Journals (Sweden)

    Tine Gregersen

    2012-01-01

    Full Text Available Neuroendocrine tumors are rare tumors primarily located in the gastrointestinal tract. Goblet cell carcinoid is a rare subgroup of neuroendocrine tumors located in the appendix. Neurofibromatosis type 1 is an autosomal dominant disorder caused by a mutation in the NF1 gene. Patients with neurofibromatosis type 1 have an increased incidence of typical neuroendocrine tumors, but it is unknown if this is the case with goblet cell carcinoids. We describe a patient with both neurofibromatosis type 1 and goblet cell carcinoid, that according to literature would occur in 0.00017 per million per year. This may suggest a previously unknown association between neurofibromatosis type 1 and goblet cell carcinoids.

  9. Neurofibromatosis and breast cancer: Do we need to revise the mammographic screening schedule in patients of neurofibromatosis?

    Directory of Open Access Journals (Sweden)

    Dinesh Pradhan

    2017-01-01

    Full Text Available Neurofibromatosis type 1 (NF-1 is a neurocutaneous syndrome with autosomal dominant mode of inheritance and has a high propensity to develop benign and malignant nervous system tumors. Although uncommon, case reports describing the association of NF-1 and breast cancer are available in the literature. We illustrate one such case of NF-1, with no family history of the disorder and presenting with multifocal invasive carcinoma of the right breast, in an attempt to describe the association between these two entities. We also attempt to extensively review the current literature on the subject. Since patients with NF-1 are at an increased risk of developing breast cancer, we recommend strict adherence to careful clinical breast examination and annual screening mammographic examination starting at 40 years of age in all patients of NF-1.

  10. Statins, bone, and neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Korf Bruce R

    2008-07-01

    Full Text Available Abstract Neurofibromatosis type 1 (NF1 is a dominantly inherited multi-system disorder. Major features include pigmentary abnormalities, benign tumors of the nerve sheath (neurofibromas, malignant tumors, learning disabilities, and skeletal dysplasia. The NF1 gene functions as a tumor suppressor, but haploinsuffiency probably accounts for some aspects of the non-tumor phenotype. The protein product, neurofibromin, is a Ras GTPase-activating protein, and various Ras pathway inhibitors are being tested in preclinical models and clinical trials for effectiveness in treating NF1 complications. This month in BMC Medicine, a paper by Kolanczyk et al describes a preclinical mouse model for tibial dysplasia and provides evidence that the drug lovastatin – in use to treat cardiovascular disease – may be beneficial, opening the door to clinical trials in humans.

  11. Learning disability and oligodendrocyte myelin glycoprotein (OMGP) gene in neurofibromatosis type 1.

    Science.gov (United States)

    Terzi, Yunus Kasim; Oğuzkan-Balci, Sibel; Anlar, Banu; Erdoğan-Bakar, Emel; Ayter, Sükriye

    2011-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease where phenotypic heterogeneity is explained by the effect of modifier genes. Thirty to 65% of patients have learning disability. The oligodendrocyte myelin glycoprotein (OMGP) gene located within the neurofibromatosis type 1 (NF1) gene might affect the phenotype of learning disability because it is expressed in the brain, and OMGP gene mutations have been associated with cognitive disturbances. We analyzed the OMGP gene in NF1 patients with and without learning disability (n = 50 each) and healthy controls (n = 100). The allele distribution of OMGP62 polymorphism was not significantly different between the groups (p = 0.447). These results do not support a relationship between the OMGP gene and the learning disability phenotype observed in NF1. Other modifying genes, post-translational modifications or receptor interactions might be involved in the phenotypic variability of NF1.

  12. A Giant Lumbar Pseudomeningocele in a Patient with Neurofibromatosis Type 1: A Case Report

    Science.gov (United States)

    Iacoangeli, Maurizio; Ruscelli, Paolo; Della Costanza, Martina; Nasi, Davide; Scerrati, Massimo

    2017-01-01

    This is a rare case of giant lumbar pseudomeningocele with intra-abdominal extension in patient with neurofibromatosis type 1 (NF1). The patient's clinical course is retrospectively reviewed. A 34-year-old female affected by NF1 was referred to our institution for persistent low back pain and MRI diagnosis of pseudomeningocele located at L3 level with paravertebral extension. From the first surgical procedure by a posterior approach until the relapse of the pseudomeningocele documented by MRI, the patient underwent two subsequent posterior surgical procedures to repair the dural sac defect with fat graft and fibrin glue. One month after the third operation, the abdominal MRI showed a giant intra-abdominal pseudomeningocele causing compression of visceral structures. The patient was asymptomatic. The pseudomeningocele was treated with an anterior abdominal approach and the use of the acellular dermal matrix (ADM) sutured directly on the dural defect on the anterolateral wall of the spinal canal. After six months of follow-up the MRI showed no relapse of the pseudomeningocele. Our case highlights the possible use of ADM as an effective and safe alternative to the traditional fat graft to repair challenging and large dural defects. PMID:28250774

  13. A Giant Lumbar Pseudomeningocele in a Patient with Neurofibromatosis Type 1: A Case Report

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    Mauro Dobran

    2017-01-01

    Full Text Available This is a rare case of giant lumbar pseudomeningocele with intra-abdominal extension in patient with neurofibromatosis type 1 (NF1. The patient’s clinical course is retrospectively reviewed. A 34-year-old female affected by NF1 was referred to our institution for persistent low back pain and MRI diagnosis of pseudomeningocele located at L3 level with paravertebral extension. From the first surgical procedure by a posterior approach until the relapse of the pseudomeningocele documented by MRI, the patient underwent two subsequent posterior surgical procedures to repair the dural sac defect with fat graft and fibrin glue. One month after the third operation, the abdominal MRI showed a giant intra-abdominal pseudomeningocele causing compression of visceral structures. The patient was asymptomatic. The pseudomeningocele was treated with an anterior abdominal approach and the use of the acellular dermal matrix (ADM sutured directly on the dural defect on the anterolateral wall of the spinal canal. After six months of follow-up the MRI showed no relapse of the pseudomeningocele. Our case highlights the possible use of ADM as an effective and safe alternative to the traditional fat graft to repair challenging and large dural defects.

  14. Cognitive functions in neurofibromatosis type 1 patients and unaffected siblings.

    Science.gov (United States)

    Erdoğan-Bakar, Emel; Cinbiş, Mine; Ozyürek, Hamit; Kiriş, Nurcihan; Altunbaşak, Sakir; Anlar, Banu

    2009-01-01

    Attention, learning, and perceptual problems have been reported at various degrees and rates in neurofibromatosis type 1 (NF1). We aimed to define the cognitive profiles frequently associated with NF1. Children and adolescents with NF1 (n=58) were tested using Wechsler Intelligence Scales for Children-Revised (WISC-R), Judgment of Line Orientation, and Bender Visual-Motor Gestalt tests. Comparison groups were unaffected siblings of NF1 patients (n=20), children with attention deficit and hyperactivity disorder (ADHD, n=40), and normal children (n=40). No difference was found between familial or sporadic NF1 cases. Seventeen/58 (29%) of NF1 cases had a full scale IQ80 (n=27) scored lower in WISC-R subtests measuring visual perception when compared to a healthy control group of similar intelligence, and lower in arithmetic but better in Bender-Gestalt and Judgment of Line Orientation tests when compared to an ADHD group of similar intelligence. These results indicate a high prevalence of mental retardation in a clinical NF1 series. NF1 patients who have normal intelligence may have impaired visual perception, but their visual perceptual problems are less than in ADHD. The tendency of unaffected siblings of NF1 patients to have mildly but consistently low test scores compared to healthy controls needs to be studied further for underlying genetic or environmental factors.

  15. Fatal glioblastoma multiforme in a patient with neurofibromatosis type I: the dilemma of systematic medical follow-up.

    NARCIS (Netherlands)

    Distelmaier, F.; Fahsold, R.; Reifenberger, G.; Messing-Juenger, M.; Schaper, J.; Schneider, D.T.; Gobel, U.; Mayatepek, E.; Rosenbaum, T.

    2007-01-01

    INTRODUCTION: Neurofibromatosis type I (NF1) is one of the most prevalent genetic diseases of the nervous system. Although the majority of NF1 patients are only mildly affected, the risk of developing malignancies is significantly increased in this population. CASE REPORT: Here, we present a 9-year-

  16. The relation of emotion recognition and social behavioral problems in children with neurofibromatosis type 1: An explorative study

    NARCIS (Netherlands)

    Coenen, Maraike; Aarnoudse, Cecilia; Boon, Maartje; Veenstra, Wencke

    2014-01-01

    OBJECTIVE: Children with neurofibromatosis type 1 (NF1) often show cognitive and behavioral problems (Martin et al., 2011). Huijbregts et al. (2010) investigated cognitive problems in children with NF1 focusing on social information processing. They found that bottom-up as well as top-down processes

  17. Using a Virtual Classroom Environment to Describe the Attention Deficits Profile of Children with Neurofibromatosis Type 1

    Science.gov (United States)

    Gilboa, Yafit; Rosenblum, Sara; Fattal-Valevski, Aviva; Toledano-Alhadef, Hagit; Rizzo, Albert; Josman, Naomi

    2011-01-01

    The objectives of this study were to describe the nature of the attention deficits in children with Neurofibromatosis type 1 (NF1) in comparison with typically developing (TD) children, using the Virtual Classroom (VC), and to assess the utility of this instrument for detecting attention deficits. Twenty-nine NF1 children and 25 age-and…

  18. Mammalian target of rapamycin inhibitor abrogates abnormal osteoclastogenesis in neurofibromatosis type 1

    Institute of Scientific and Technical Information of China (English)

    LIU Ning; XU Ning; WEI Li-hui; CHAI Guo-lin

    2013-01-01

    Background Neurofibromatosis type 1 (NF1) is the most common genetic syndrome predisposing patients to various tumors due to dysregulation of the Ras signaling pathway.Recent research has shown NF1 patients also suffer a spectrum of bone pathologies.The pathogenesis of NF1 bone diseases is largely unknown.There is no current treatment.By Nf1 heterozygote (Nf1+/-) mice and Nf1 conditional knockout mice,we and other groups demonstrated abnormal osteoblast and osteoclast function due to dysregulation of Ras signaling.However,the specific downstream effector pathways linked to NF1 abnormal osteoblastogenesis and osteoclastogenesis have not been defined.In this study,we investigated the Ras downstream effector related with NF1 bone disease.Methods We used Nf1+/+ and Nf1+/-mice as normal and NF1 models.Bone stromal cells extracted from Nf1+/+ and Nf1+/-mice were induced osteoclasts.The osteoclast cell was stained by tartrate resistant acid phosphatase staining.The osteoclast cell number was counted and the surface area of osteoclast cells was calculated under the microscope.The mRNA of mammalian target of rapamycin (mTOR) was determined by quantitative reverse-transcription-polymerase chain reaction.The presence of ribosomal protein S6 kinase was determined by Western blotting.Results Compared with Nf1+/+ mice,Nf1+/-mice had about 20% more of osteoclast cells.These osteoclast cells werelarger in size with more nuclei.Hyperactive mTOR was detected in Nf1+/-osteoclast cells.Inhibition of mTOR signalingby rapamycin in Nf1+/-osteoclasts abrogated abnormalities in cellular size and number.Conclusion mTOR pathway inhibition may represent a viable therapy for NF1 bone diseases.

  19. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development

    Directory of Open Access Journals (Sweden)

    Jimann Shin

    2012-11-01

    Neurofibromatosis type 1 (NF1 is a common, dominantly inherited genetic disorder that results from mutations in the neurofibromin 1 (NF1 gene. Affected individuals demonstrate abnormalities in neural-crest-derived tissues that include hyperpigmented skin lesions and benign peripheral nerve sheath tumors. NF1 patients also have a predisposition to malignancies including juvenile myelomonocytic leukemia (JMML, optic glioma, glioblastoma, schwannoma and malignant peripheral nerve sheath tumors (MPNSTs. In an effort to better define the molecular and cellular determinants of NF1 disease pathogenesis in vivo, we employed targeted mutagenesis strategies to generate zebrafish harboring stable germline mutations in nf1a and nf1b, orthologues of NF1. Animals homozygous for loss-of-function alleles of nf1a or nf1b alone are phenotypically normal and viable. Homozygous loss of both alleles in combination generates larval phenotypes that resemble aspects of the human disease and results in larval lethality between 7 and 10 days post fertilization. nf1-null larvae demonstrate significant central and peripheral nervous system defects. These include aberrant proliferation and differentiation of oligodendrocyte progenitor cells (OPCs, dysmorphic myelin sheaths and hyperplasia of Schwann cells. Loss of nf1 contributes to tumorigenesis as demonstrated by an accelerated onset and increased penetrance of high-grade gliomas and MPNSTs in adult nf1a+/−; nf1b−/−; p53e7/e7 animals. nf1-null larvae also demonstrate significant motor and learning defects. Importantly, we identify and quantitatively analyze a novel melanophore phenotype in nf1-null larvae, providing the first animal model of the pathognomonic pigmentation lesions of NF1. Together, these findings support a role for nf1a and nf1b as potent tumor suppressor genes that also function in the development of both central and peripheral glial cells as well as melanophores in zebrafish.

  20. Left Ulnar Artery Pseudoaneurysm and Left Hand Swelling Simulated by Elephantiasis in a Patient with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Ta-Pin Lee

    2017-06-01

    Full Text Available Elephantiasis is a condition featured by gross enlargement of body parts to massive proportions. Neurofibromatosis type 1 (NF1 is a multisystem genetic disorder. Vascular anomaly is one among the complications of NF1. We report a case of NF1 who had a left hand vascular pseudoaneurysm with left hand swelling mimicking elephantiasis. The characteristics of sonography make it an excellent imaging modality to investigate this sort of superficial vascular lesion.

  1. Malignant peripheral nerve sheath tumor of the cervical vagus nerve in a neurofibromatosis type 1 patient - An unusual presentation

    Directory of Open Access Journals (Sweden)

    Ashok Gupta

    2010-07-01

    Full Text Available Malignant peripheral nerve sheath tumors (MPNST’S of the head and neck comprise 2% to 6% of head and neck sarcomas. These tumors may arise as sporadic variants or in patients with neurofibromatosis (NF. Development of these MPNST’s is one of the serious complications of neurofibromatosis type 1(NF1. To our knowledge there are only two reported cases of MPNST’s arising in the cervical vagal nerve, occurring in NF1 patients. We present here an NF1 patient who developed an MPNST of the cervical vagus nerve and presented only with a cervical swelling and hoarseness.

  2. Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1.

    Science.gov (United States)

    Toelle, Sandra P; Poretti, Andrea; Weber, Peter; Seute, Tatjana; Bromberg, Jacoline E C; Scheer, Ianina; Boltshauser, Eugen

    2015-12-01

    Unidentified bright objects (UBO) and tumors are well-known cerebellar abnormalities in neurofibromatosis type 1 (NF1). Literature reports on malformative cerebellar anomalies in neurofibromatosis type 1 (NF1), however, are scant. We retrospectively studied the clinical and neuroimaging findings of 5 patients with NF1 (4 females, age 6 to 29 years at last follow-up) and cerebellar anomalies. Cerebellar symptoms on neurological examination were mild or even not evident whereas learning disabilities were more or less pronounced in four patients. Two patients had cerebellar hypoplasia (diffusely enlarged cerebellar interfoliar spaces) and three cerebellar dysmorphias involving mainly one cerebellar hemisphere. In NF1, malformative cerebellar anomalies are rare (estimated prevalence of about 1%), but most likely underestimated and easily overlooked, because physicians tend to focus on more prevalent, obvious, and well-known findings such as optic pathway gliomas, other tumors, and UBO. This kind of cerebellar anomaly in NF1 has most likely a malformative origin, but the exact pathogenesis is unknown. The individual clinical significance is difficult to determine. We suggest that cerebellar anomalies should be systematically evaluated in neuroimaging studies of NF1 patients.

  3. NF1 Signal Transduction and Vascular Dysfunction

    Science.gov (United States)

    2014-05-01

    the effects of losing a second allele of NF1 in the vascular endothelium of the adult mouse. This will be the first model of NF1 loss in the... adult endothelium and can serve as a model system for investigation of both cardiovascular effects and the tumor microenvironment. Body: Aim 1...would be to try and determine if there were defects in TGF-b signaling (Smad activation/EndMT) prior to doing a wholesale catalog of all the

  4. Multiple or familial café-au-lait spots is neurofibromatosis type 6: clarification of a diagnosis.

    Science.gov (United States)

    Madson, Justin G

    2012-05-15

    A café-au-lait macule (CALM) is an evenly pigmented macule or patch of variable size. Solitary CALMs are common birthmarks in up to 2.5 percent of normal neonates and their incidence rises to up to 25 percent in preschool-aged children. Two or more CALMs occur much less frequently. Multiple lesions may warrant investigation to identify an underlying disease including neurofibromatosis types 1 (NF1), neurofibromatosis type 2, McCune-Albright syndrome, and neurofibromatosis type 1-like syndrome. Considered a hallmark and diagnostic criteria for NF1 is the presence of 6 or more CALMs greater than 0.5 cm in prepubertal individuals. Rare reports describe families which demonstrate the phenomenon of multiple CALMs without other stigmata of NF1 or evidence of other systemic disease. Herein is a description of the condition and justification for this entity to be named Neurofibromatosis type 6.

  5. Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene.

    Science.gov (United States)

    Cunha, Karin Soares; Oliveira, Nathalia Silva; Fausto, Anna Karoline; de Souza, Carolina Cruz; Gros, Audrey; Bandres, Thomas; Idrissi, Yamina; Merlio, Jean-Philippe; de Moura Neto, Rodrigo Soares; Silva, Rosane; Geller, Mauro; Cappellen, David

    2016-12-17

    Neurofibromatosis 1 (NF1) is one of the most common genetic disorders and is caused by mutations in the NF1 gene. NF1 gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding NF1 regions. Hybridization capture-based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole NF1 gene (exons and introns) from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11). We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G). Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire NF1 gene (exons and introns) for different types of pathogenic variations, including the deep intronic splicing mutations.

  6. Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional Nf1 to apoptosis in the absence of protein kinase C.

    Science.gov (United States)

    Ganapathy, Suthakar; Fagman, Johan B; Shen, Ling; Yu, Tianqi; Zhou, Xiaodong; Dai, Wei; Makriyannis, Alexandros; Chen, Changyan

    2016-12-20

    Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.

  7. Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene

    Science.gov (United States)

    Cunha, Karin Soares; Oliveira, Nathalia Silva; Fausto, Anna Karoline; de Souza, Carolina Cruz; Gros, Audrey; Bandres, Thomas; Idrissi, Yamina; Merlio, Jean-Philippe; de Moura Neto, Rodrigo Soares; Silva, Rosane; Geller, Mauro; Cappellen, David

    2016-01-01

    Neurofibromatosis 1 (NF1) is one of the most common genetic disorders and is caused by mutations in the NF1 gene. NF1 gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding NF1 regions. Hybridization capture-based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole NF1 gene (exons and introns) from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11). We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G). Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire NF1 gene (exons and introns) for different types of pathogenic variations, including the deep intronic splicing mutations. PMID:27999334

  8. Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene

    Directory of Open Access Journals (Sweden)

    Karin Soares Cunha

    2016-12-01

    Full Text Available Neurofibromatosis 1 (NF1 is one of the most common genetic disorders and is caused by mutations in the NF1 gene. NF1 gene mutational analysis presents a considerable challenge because of its large size, existence of highly homologous pseudogenes located throughout the human genome, absence of mutational hotspots, and diversity of mutations types, including deep intronic splicing mutations. We aimed to evaluate the use of hybridization capture-based next-generation sequencing to screen coding and noncoding NF1 regions. Hybridization capture-based next-generation sequencing, with genomic DNA as starting material, was used to sequence the whole NF1 gene (exons and introns from 11 unrelated individuals and 1 relative, who all had NF1. All of them met the NF1 clinical diagnostic criteria. We showed a mutation detection rate of 91% (10 out of 11. We identified eight recurrent and two novel mutations, which were all confirmed by Sanger methodology. In the Sanger sequencing confirmation, we also included another three relatives with NF1. Splicing alterations accounted for 50% of the mutations. One of them was caused by a deep intronic mutation (c.1260 + 1604A > G. Frameshift truncation and missense mutations corresponded to 30% and 20% of the pathogenic variants, respectively. In conclusion, we show the use of a simple and fast approach to screen, at once, the entire NF1 gene (exons and introns for different types of pathogenic variations, including the deep intronic splicing mutations.

  9. Scoliosis in a Case of Neurofibromatosis Type 1

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    Özlem SOLAK

    2010-05-01

    Full Text Available Neurofibromatosis Type 1 (NF1 is a multisystemic disease, manifesting as abnormalities ofthe nervous tissue, bones, soft tissue, and skin. The entity is dominantly inherited and affects 1in 4000 individuals. Cafe-au-lait spots, peripheral neurofibromas, Lisch nodules and axillaryfreckling are the characteristics of NF1. Bone abnormalities are usually observed in NF1. Scoliosis is a skeletal anomaly reported to beassociated with NF1. We made a diagnosis of NF1 and scoliosis secondary to NF1 in our 26-year-old male case with complaints of low back pain, a mass on his left hip beginning 10 yearsago and growing and with cafe-au-lait spots on his back. We think that, in daily practice, it isimportant to look for cafe-au-lait spots with inspection in the patients coming with the complaintof low back pain and when these spots are observed a diagnosis of NF1 should be suspected.Besides, we wanted to emphasize that scoliosis should be searched in the patients with adiagnosis of NF1 and low back pain.

  10. Confirmation of mutation landscape of NF1-associated malignant peripheral nerve sheath tumors.

    Science.gov (United States)

    Sohier, Pierre; Luscan, Armelle; Lloyd, Angharad; Ashelford, Kevin; Laurendeau, Ingrid; Briand-Suleau, Audrey; Vidaud, Dominique; Ortonne, Nicolas; Pasmant, Eric; Upadhyaya, Meena

    2017-05-01

    The commonest tumors associated with neurofibromatosis type 1 (NF1) are benign peripheral nerve sheath tumors, called neurofibromas. Malignant transformation of neurofibromas into aggressive MPNSTs may occur with a poor patient prognosis. A cooperative role of SUZ12 or EED inactivation, along with NF1, TP53, and CDKN2A loss-of-function, has been proposed to drive progression to MPNSTs. An exome sequencing analysis of eight MPNSTs, one plexiform neurofibroma, and seven cutaneous neurofibromas was undertaken. Biallelic inactivation of the NF1 gene was observed in the plexiform neurofibroma and the MPNSTs, underlining that somatic biallelic NF1 inactivation is likely to be the initiating event for plexiform neurofibroma genesis, although it is unlikely to be sufficient for the subsequent MPNST development. The majority (5/8) of MPNSTs in our analyses demonstrated homozygous or heterozygous deletions of CDKN2A, which may represent an early event following NF1 LOH in the malignant transformation of Schwann cells from plexiform neurofibroma to MPNST. Biallelic somatic alterations of SUZ12 was also found in 4/8 MPNSTs. EED biallelic alterations were detected in 2 of the other four MPNSTs, with one tumor having a homozygous EED deletion. A missense mutation in the chromatin regulator KDM2B was also identified in one MPNST. No TP53 point mutations were found in this study, confirming previous data that TP53 mutations may be relatively rare in NF1-associated MPNSTs. Our study confirms the frequent biallelic inactivation of PRC2 subunits SUZ12 and EED in MPNSTs, and suggests the implication of KDM2B.

  11. Evaluation of tibial osteopathy occurrence in neurofibromatosis type 1 Italian patients.

    Science.gov (United States)

    Morcaldi, Guido; Clementi, Maurizio; Lama, Giuliana; Gabrielli, Orazio; Vannelli, Silvia; Virdis, Raffaele; Vivarelli, Rossella; Boero, Silvio; Bonioli, Eugenio

    2013-05-01

    Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disorder characterized by high penetrance, widely variable expressivity and occurrence of specific skeletal changes such as tibial osteopathy (TO). We collected data on patients referred to the Italian Neurofibromatosis Study Group in order to compare clinical features between 49 NF1 patients with TO, and 98 age-matched NF1 patients without TO, and to determine whether the presence of TO is associated with a different risk of developing the typical NF1 complications. We assessed both groups for: age at diagnosis of NF1, gender distribution, family history, gender inheritance, presence of scoliosis, sphenoid wing osteopathy, other skeletal abnormalities, macrocrania, hydrocephalus, plexiform neurofibromas, tumors, optic pathway gliomas, T2H (high-signal intensity areas on T2 weighted brain MRI), epilepsy, headache, mental retardation, cardiovascular malformations, and Noonan phenotype. Patients of both groups were subdivided by gender and re-evaluated for these items. Statistical comparison was carried out between the two groups of patients for each feature. We collected data on type of treatment and on the clinical conditions of NF1-TO patients after follow-up. Patient's age at NF1 diagnosis was significantly younger in NF1-TO subjects compared with NF1 subjects without TO, and the incidence of T2H was significantly reduced in NF1-TO males compared with NF1 males without TO. The presence of TO does not imply that there is an increased risk of developing typical complications of NF1 (e.g., optic pathway glioma, plexiform neurofibroma, etc.), however, it does allow us to make an earlier diagnosis of NF1.

  12. [Learning disorders in neurofibromatosis type 1].

    Science.gov (United States)

    Garcia-Penas, J J

    2017-02-24

    Introduccion. Los deficits neurocognitivos y las dificultades de aprendizaje representan las complicaciones neurologicas mas frecuentes de la neurofibromatosis tipo 1 (NF1) en la edad pediatrica y son responsables de una importante morbilidad evolutiva. Los niños con NF1 muestran alteraciones en atencion, percepcion visual, lenguaje, funciones ejecutivas, logros academicos y conducta. Los estudios en modelos animales sugieren que las alteraciones de aprendizaje en la NF1 se relacionan con una potenciacion de la actividad Ras que conduce a un incremento de la inhibicion mediada por el acido gamma-aminobutirico (GABA) y a una disminucion de la potenciacion sinaptica a largo plazo. Objetivo. Describir la frecuencia, gravedad, tipologia y evolucion natural de los deficits neurocognitivos especificos de la NF1. Desarrollo. Los trastornos neurocognitivos y conductuales afectan al 50-80% de los niños con NF1. Se pueden definir tres subtipos de perfiles cognitivos en la NF1, incluyendo trastorno de aprendizaje global, trastorno especifico de aprendizaje y trastorno por deficit de atencion/hiperactividad aislado. Los deficits cognitivos mas frecuentes se relacionan con la alteracion visuoespacial, aunque tambien son importantes las alteraciones de la memoria de trabajo y de la funcion ejecutiva asociadas con la disfuncion de la corteza prefrontal. Conclusiones. Existe una gran frecuencia global de problemas cognitivos en la NF1, lo cual implica que la disfuncion neurocognitiva sea la mayor complicacion medica que afecta la calidad de vida de estos pacientes. El diagnostico y el tratamiento precoces de los trastornos de aprendizaje en estos niños son basicos para conseguir un mejor desempeño academico.

  13. Autism spectrum disorder profile in neurofibromatosis type I.

    Science.gov (United States)

    Garg, Shruti; Plasschaert, Ellen; Descheemaeker, Mie-Jef; Huson, Susan; Borghgraef, Martine; Vogels, Annick; Evans, D Gareth; Legius, Eric; Green, Jonathan

    2015-06-01

    Neurofibromatosis Type 1 (NF1) is a common autosomal dominant single-gene disorder, in which the co-occurrence of autism spectrum disorder (ASD) has attracted considerable research interest recently with prevalence estimates of 21-40%. However, detailed characterization of the ASD behavioral phenotype in NF1 is still lacking. This study characterized the phenotypic profile of ASD symptomatology presenting in 4-16 year old children with NF1 (n = 36) using evidence from parent-rated Social Responsiveness Scale and researcher autism diagnostic observation Scale-2. Compared to IQ-matched reference groups of children with autism and ASD, the NF1 profile shows overall similarity but improved eye contact, less repetitive behaviors and better language skills.

  14. A Pleural Solitary Fibrous Tumor, Multiple Gastrointestinal Stromal Tumors, Moyamoya Disease, and Hyperparathyroidism in a Patient Associated with NF1

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    Yoko Yamamoto

    2015-01-01

    Full Text Available Neurofibromatosis type 1 (NF1, also called von Recklinghausen’s disease, is a multisystemic disease caused by an alteration of the NF1 gene, a tumor suppressor located on the long arm of chromosome 17 (17q11.2. Loss of the gene function, due to a point mutation, leads to an increase in cell proliferation and the development of several tumors. We report a 60-year-old female patient manifesting hypercalcemia due to hyperparathyroidism, a solitary fibrous tumor (SFT of the pleura, multiple gastrointestinal stromal tumors (GISTs, and moyamoya disease associated with NF1. The SFT and GISTs were removed by staged operations. Then, hypercalcemia was successfully controlled after resection of the parathyroid adenoma. Based on a literature review, these combinations have never been reported, and the relevant literature is briefly discussed.

  15. Oral Metastasis of Metaplastic Breast Carcinoma in a Patient with Neurofibromatosis 1

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    Ana Paula Molina Vivas

    2014-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 has been associated with an increased risk for development of malignancy, especially malignant peripheral nerve sheath tumors. In addition, recently, literature has demonstrated an increased risk of breast cancer in women with NF1. The present paper shows a 53-year-old woman with NF1 who presented with metaplastic breast carcinoma and developed multiple metastases, including mandible. Furthermore, we reviewed the English literature, found 63 cases showing the association between NF1 and breast cancer, and added one more case. The present study demonstrated an important association between NF1 and breast cancer. Until the present time, there has been only one case of metaplastic breast carcinoma associated with NF1. Curiously, in our case the oral metastasis corresponded to sarcomatous component of metaplastic breast carcinoma.

  16. Unusual coexistence between lupus nephritis and neurofibromatosis 1: a case report and review of previous cases

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    Manoj Kumar Roy

    2015-05-01

    Full Text Available The association of Neurofibromatosis 1 (NF 1, an autosomal dominant genetic disease with autoimmune diseases like systemic lupus erythematosus is rare, five case reports are there in medical literature showing such association. Here we have documented a case of Lupus nephritis associated with Neurofibromatosis 1 diagnosed in the same setting, in a 24 years old female patient presented with oliguria, hypertension, anasarca, cafe-au-lait spots, palmer freckling, subcutaneous nodules, alopecia areata and positive family history for NF 1. [Int J Res Med Sci 2015; 3(5.000: 1277-1280

  17. Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors

    Science.gov (United States)

    Uusitalo, Elina; Kallionpää, Roope A; Kurki, Samu; Rantanen, Matti; Pitkäniemi, Janne; Kronqvist, Pauliina; Härkönen, Pirkko; Huovinen, Riikka; Carpen, Olli; Pöyhönen, Minna; Peltonen, Sirkku; Peltonen, Juha

    2017-01-01

    Background: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers. Methods: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls. Results: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population. Conclusions: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1. PMID:27931045

  18. Cerebral volumetric abnormalities in Neurofibromatosis type 1: associations with parent ratings of social and attention problems, executive dysfunction, and autistic mannerisms

    NARCIS (Netherlands)

    Huijbregts, S.C.; Loitfelder, M.; Rombouts, S.A.R.B.; Swaab, H.; Verbist, B.M.; Arkink, E.B.; Buchem, M.A. van; Veer, I.M.

    2015-01-01

    Neurofibromatosis type 1 (NF1) is a single-gene neurodevelopmental disorder, in which social and cognitive problems are highly prevalent. Several commonly observed central nervous system (CNS) abnormalities in NF1 might underlie these social and cognitive problems. Cerebral volumetric abnormalities

  19. ENUCLEATION IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1 WITH BUPHTHALMOS AND OCULAR DEFORMITY

    Directory of Open Access Journals (Sweden)

    F. Asadi-Amoli

    2007-09-01

    Full Text Available To report a case of buphthalmos with neurofibromatosis (NF-1 who suffered with blindness suffered enucleation. Physical examination & histopathology were performed. Physical examination revealed Buphthalmos & vascularized cornea with lower lid ectropion and orbital deformity. Histopathologic findings shows plexiform neurofibroma in orbital tissue with scleral wall involvement. And hamartomatous proliferation in choroid & cilliary bodies with melanocytic elements. Few NF-1 cases with buphthalmos have been reported. But cases with complicationg buphthalmos (retinal Detachment & optic nerve Atrophy suffering enucleation are very rare.

  20. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Science.gov (United States)

    Makino, Shinji; Endoh, Katsuhisa; Tampo, Hironobu

    2013-01-01

    Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1) associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years. PMID:23781366

  1. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Directory of Open Access Journals (Sweden)

    Shinji Makino

    2013-01-01

    Full Text Available Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1 associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years.

  2. Pathological fracture dislocation of the acetabulum in a patient with neurofibromatosis-1

    OpenAIRE

    Balaji Saibaba; Ramesh Kumar Sen; Manish Sharma; Uma Nahar

    2016-01-01

    Skeletal neurofibromatosis (NF) commonly manifests as scoliosis and tibial dysplasias. NF affecting the pelvic girdle is extremely rare. Pathological fracture of the acetabulum leading to anterior hip dislocation in a patient with NF-1 has never been reported in the literature. The paper presents the clinical symptomatology, the course of management and the successful outcome of such a rare case of NF-1. Histopathological and immunohistochemistry studies showing abundant spindle cells, which ...

  3. Multiple solid pilocytic astrocytomas in cerebleiium with neurofibromatosis type: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seo Young; Kim, Myung Soon; Kim, Young Ju [Dept. of Radiology, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju (Korea, Republic of)

    2014-02-15

    Pilocytic astrocytoma usually has a classic imaging manifestation of a solitary, cyst-like mass with a strong contrast-enhancing mural nodule. There is only one published report so far of multiple solid and cyst type pilocytic astrocytomas in the cerebellum in neurofibromatosis type 1 (NF1) patient from the United States in 2007. We report a case of pilocytic astrocytoma presenting with only solid, multiple pilocytic astrocytomas in the cerebellum in NF1 patient.

  4. Pseudoarthrosis of the hand in neurofibromatosis type 1: a case report.

    Science.gov (United States)

    İncecik, Faruk; Hergüner, M Özlem; Ballı, Tuğsan; Altunbaşak, Şakir

    2013-01-01

    Neurofibromatosis (NF) is a disorder with a wide spectrum of clinical manifestations. Here, we describe a 16-year-old boy with NF1 who had pseudoarthrosis of the 4th and 5th fingers of the left hand. He had specific cutaneous lesions and Lisch nodules in the iris. Because NF1 affects multiple organ systems, patients are likely to benefit most from a multidisciplinary treatment strategy.

  5. The soft-tissue manifestations of neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Hillier, J.C. [Department of Clinical Radiology, Chelsea and Westminster Hospital, London (United Kingdom)]. E-mail: julia.hillier@chelwest.nhs.uk; Moskovic, E. [Department of Clinical Radiology, Royal Mardsen Hospital, London (United Kingdom)

    2005-09-01

    The radiological appearances of neurofibromatosis type 1 (NF-1) are numerous and variable, because of the widespread presence of peripheral nerves. Knowledge of this variability can prevent unnecessary intervention. For example, occasionally lesions can be misinterpreted and biopsies performed unnecessarily. Thus, familiarity with the manifestations of this disease and the spectrum of associated abnormalities is an important part of the radiologist's armamentarium. This paper explores the manifold radiological appearances of extracranial NF-1 as experienced by the Sarcoma and Soft Tissue Tumour Unit at the Royal Marsden Hospital.

  6. Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1

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    Baris Gundogdu

    2016-01-01

    Full Text Available Ankylosing spondylitis (AS is a systemic disease primarily characterized by the inflammation of sacroiliac joints and axial skeleton. Neurofibromatosis type 1 (NF1 is a multisystem genetic disease which is characterized by cutaneous findings, most importantly café-au-lait spots and axillary freckling, by skeletal dysplasia, and by the growth of both benign and malignant nervous system neoplasms, most notably benign neurofibromas. In this case report, we present a 43-year-old male with AS and NF1.

  7. Unroofed coronary sinus in a patient with neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Luciano Pereira Bender

    2013-12-01

    Full Text Available OBJECTIVE: To report the uncommon association between neurofibromatosis type 1 (NF1 and unroofed coronary sinus. CASE DESCRIPTION: Girl with four years and six months old who was hospitalized for heart surgery. The cardiac problem was discovered at four months of life. On physical examination, the patient presented several café-au-lait spots in the trunk and the limbs and freckling of the axillary and groin regions. Her father had similar skin findings, suggesting the NF1 diagnosis. The cardiac evaluation by echocardiography disclosed an atrial septal defect of unroofed coronary sinus type. This cardiac finding was confirmed at surgery. The procedure consisted of the atrial septal defect repair with autologous pericardium. COMMENTS: NF1 is a common autosomal dominant disorder caused by mutations in the NF1 gene. Among the NF1 findings, congenital heart defects are considered unusual. In the literature review, there was no association between NF1 and unroofed coronary sinus, which is a rare cardiac malformation, characterized by a communication between the coronary sinus and the left atrium, resultant from the partial or total absence of the coronary sinus roof. It represents less than 1% of atrial septal defect cases. More reports are important to determine if this association is real or merely casual, since NF1 is a common condition.

  8. Personality profiles of children and adolescents with neurofibromatosis type 1.

    Science.gov (United States)

    Prinzie, P; Descheemaeker, M J; Vogels, A; Cleymans, T; Haselager, G J T; Curfs, L M G; Hellinckx, W; Onghena, P; Legius, E; van Lieshout, C F M; Fryns, J-P

    2003-04-01

    The personality profile of 44 youngsters (24 males, 20 females; mean age 11 years, 3 months) with neurofibromatosis type 1 (NF1) was compared with a group of 220 non-NF1 control youngsters (matched on age and gender). Personality characteristics of each youngster were rated by both parents, using the California Child Q-set (CCQ); [Block and Block, 1980]. The scores on eight personality dimensions were compared, i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability, and Dependency. Moreover, personality of NF1 youngsters was related to IQ level, severity of medical problems, the presence or absence of visible cosmetic disfiguring, and de novo versus familial origin of NF1. The personality profile of NF1 youngsters was markedly different from the non-NF1 youngsters. Compared to the 220 control children, they were equally agreeable, but less conscientious, less emotionally stable, less open for new experience, with less motor activity, and more extravert, more dependent, and more irritable. Personality characteristics were similar for children with maternally or paternally inherited NF1, or for children with a new mutation. There was no association with gender, the severity of medical and cosmetic problems, and IQ. Copyright 2003 Wiley-Liss, Inc.

  9. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism.

    Science.gov (United States)

    Trevisson, E; Forzan, M; Salviati, L; Clementi, M

    2014-04-01

    Neurofibromatosis type 1 (NF1) is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR-RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in neurofibromatosis 1, but it has important implications for genetic counseling.

  10. Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice.

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    Rana Mroue

    2015-05-01

    Full Text Available Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1 to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis.

  11. TAGLN expression is upregulated in NF1-associated malignant peripheral nerve sheath tumors by hypomethylation in its promoter and subpromoter regions.

    Science.gov (United States)

    Park, Gun-Hoo; Lee, Su-Jin; Yim, Hyunee; Han, Jae-Ho; Kim, Hyon J; Sohn, Young-Bae; Ko, Jung Min; Jeong, Seon-Yong

    2014-10-01

    Neurofibromatosis type 1 (NF1) caused by NF1 gene mutation is a commonly inherited autosomal dominant disorder. Malignant peripheral nerve sheath tumors (MPNSTs), a type of aggressive sarcoma, are a major cause of mortality in NF1 patients. The malignant transformation of benign plexiform neurofibromas (PNs) to MPNSTs is a marked peculiarity in NF1 patients, yet the pathogenesis remains poorly understood. We found that an actin-associated protein transgelin (SM22) was highly expressed in NF1-deficient MPNST tissues compared to NF1-deficient PN tissues using immunohistological staining and primary cultured MPNST cells in western blot analysis. We further found that this transgelin upregulation was caused by increased transcriptional expression of the TAGLN gene encoding transgelin. Comparison of DNA methylation values in the promoter and subpromoter regions of the TAGLN gene in three types of NF1-deficient primary-cultured cells, derived from an NF1 patient's normal phenotype, a benign PN and MPNST tissues, revealed that the TAGLN gene was hypomethylated in the MPNST cells. Next, to determine the functional role of transgelin in MPNST pathogenesis, we manipulated the TAGLN gene expression and investigated the alteration of the RAS-mitogen-activated protein kinase (MAPK) signaling pathway in the normal-phenotypic and malignant tumor cells. The downregulation of TAGLN expression in NF1-deficient MPNST tumor cells through the treatment of the small interfering RNA resulted in a decrease in the RAS activation (GTP-RAS) and the downstream ERK1/2 activation (phosphorylated ERK1/2), while the overexpression of TAGLN in normal-phenotypic NF1-deficient cells caused an increase in RAS and ERK1/2 activation. These results indicate that upregulation of transgelin caused by hypomethylation of the TAGLN gene is closely involved in tumor progression in NF1.

  12. Learning about Neurofibromatosis

    Science.gov (United States)

    ... for the genetic terms used on this page Learning About Neurofibromatosis What is neurofibromatosis? What are the ... developmental abnormalities and/or increased chances of having learning disabilities. Other forms of NF, where the symptoms ...

  13. [Neuropsychological performance in neurofibromatosis type 1].

    Science.gov (United States)

    Hernández Del Castillo, Lilia; Martínez Bermejo, Antonio; Portellano Pérez, José Antonio; Tirado Requero, Pilar; Garriz Luis, Alexandra; Velázquez Fragua, Ramón

    2017-08-01

    Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder. In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children. A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups. The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding. The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. Neurofibromatosis, stroke and basilar impression: case report

    Directory of Open Access Journals (Sweden)

    PIOVESAN ELCIO JULIATO

    1999-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 can virtually affect any organ, presenting most frequently with "cafe au lait" spots and neurofibromas. Vasculopathy is a known complication of NF1, but cerebrovascular disease is rare. We report the case of a 51-year-old man admitted to the hospital with a history of stroke four months before admission. On physical examination, he presented various "cafe au lait" spots and cutaneous neurofibromas. Neurologic examination demonstrated right-sided facial paralysis, right-sided hemiplegia, and aphasia. Computed tomography scan of head showed hypodense areas in the basal ganglia and centrum semiovale. Radiographs of cranium and cervical spine showed basilar impression. Angiography revealed complete occlusion of both vertebral and left internal carotid arteries, and partial stenosis of the right internal carotid artery. A large network of collateral vessels was present (moyamoya syndrome. It is an uncommon case of occlusive cerebrovascular disease associated with NF1, since most cases described in the literature are in young people, and tend to spare the posterior cerebral circulation. Basilar impression associated with this case may be considered a pure coincidence, but rare cases of basilar impression and NF1 have been described.

  15. Pediatric schwannomatosis, a rare but distinct form of neurofibromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Anna K. [University of Tennessee Health Science Center, Department of Radiology, Le Bonheur Children' s Hospital, Memphis, TN (United States); Egelhoff, John C.; Curran, John G. [Phoenix Children' s Hospital, Department of Radiology, Phoenix, AZ (United States); Thomas, Bobby

    2016-03-15

    Schwannomatosis is the third major form of neurofibromatosis, distinct from neurofibromatosis type 2 (NF2) and type 1 (NF1). This condition is rare with a variable phenotypic presentation and complex molecular and genetic findings. In this case, a previously healthy teenager was found to have multiple spinal lesions and an enhancing right parotid mass on MRI. On extensive further work-up, this patient met the existing clinical criteria for schwannomatosis. This case report aims to review the clinical features and current diagnostic criteria for schwannomatosis and compare it to NF1 and NF2. Special emphasis will be placed on imaging features that should prompt the radiologist to suggest this rare diagnosis. (orig.)

  16. RAS/MEK-independent gene expression reveals BMP2-related malignant phenotypes in the Nf1-deficient MPNST.

    Science.gov (United States)

    Sun, Daochun; Haddad, Ramsi; Kraniak, Janice M; Horne, Steven D; Tainsky, Michael A

    2013-06-01

    Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery.

  17. The haploinsufficient hematopoietic microenvironment is critical to the pathological fracture repair in murine models of neurofibromatosis type 1.

    Directory of Open Access Journals (Sweden)

    Xiaohua Wu

    Full Text Available Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1, a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis. We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs and/or their progenies. This is replicated in two animal models of NF1, PeriCre(+;Nf1(flox/- and Col2.3Cre(+;Nf1(flox/- mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.

  18. Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1

    OpenAIRE

    Baris Gundogdu; Servet Yolbas; Ahmet Yildirim; Murat Gonen; Suleyman Serdar Koca

    2016-01-01

    Ankylosing spondylitis (AS) is a systemic disease primarily characterized by the inflammation of sacroiliac joints and axial skeleton. Neurofibromatosis type 1 (NF1) is a multisystem genetic disease which is characterized by cutaneous findings, most importantly café-au-lait spots and axillary freckling, by skeletal dysplasia, and by the growth of both benign and malignant nervous system neoplasms, most notably benign neurofibromas. In this case report, we present a 43-year-old male with AS an...

  19. Endovascular treatment for bilateral vertebral arteriovenous fistulas in neurofibromatosis 1.

    Science.gov (United States)

    Siddhartha, W; Chavhan, Govind B; Shrivastava, Manish; Limaye, Uday S

    2003-12-01

    We report a rare case of a 36-year-old woman with neurofibromatosis 1 (NF1) with bilateral vertebro-vertebral arteriovenous fistulas. The patient presented with quadriparesis and had neck pain. Angiography revealed vertebral arteriovenous fistulas bilaterally with dilated epidural venous plexuses compressing the cervical cord resulting in quadriparesis. Endovascular treatment using coils and balloons resulted in successful occlusion of both fistulas. At 6-months postembolization, the patient had improved significantly and is now able to walk with support.

  20. Role of autocrine osteopontin in promoting multiple functions of murine Nf1+/-osteoclast%自分泌骨桥蛋白在Nf1+/-小鼠破骨细胞功能增强中的作用

    Institute of Scientific and Technical Information of China (English)

    李会杰; 刘亚玲; 井永敏; 张英泽; 王振昊; 闫金成

    2013-01-01

    Objective To detect the osteopontin (OPN) autocrine function of the osteoclasts in neurofibromatosis type 1 heterozygote (Nfl+/-) and wild type (Nfl+/+) mice.Test the osteoclasts function of neurofibromatosis type 1 heterozygote (Nfl+/-) and wild type (Nil+/+) mice with exogenous neutralizing OPN antibody,analysis the role of autocrine OPN in the hyperfunction of osteoclast in neurofibromatosis type 1.Methods Culture the low density bone marrow cells from Nfl heterozygote (Nfl+/-) and wild type (Nfl+/+) mice (4-6 weeks old) with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand(RANKL),Measure.the OPN concentration in osteoclast culture superenant with ELISA.Culture the low density bone marrow cells from Nf1+/-and Nf1+/+ mice with or without exogenous neutralizing antibody for OPN.The function of osteoclasts and osteoclast progenitors in formation,migration,adhesion,and bone absorption were tested.Results A significantly higher concentration of OPN was detected in the Nf1+/-osteoclast culture media as compared to that of wild type.In control,Osteoclast functions,including migration,adhesion,and bone resorption of Nf1 +/-were higher than that of wild type.Addition OPN neutralizing antibody to the Nf1+/-OCL significantly reduced OCL formation.Neutralizing OPN antibody diminished both wild type and Nf1+/-OCL adhensiontion,Anti-OPN minimized OCL migration in both wild type and Nf1 +/-OCL cultures as measured by the transwell assays.Neutralizing OPN antibody diminished both wild type and Nf1+/-OCL pit formation,P>0.05 for comparing Nfl+/-vs.wild type OCLs with anti-OPN antibody.Conclusion The hyperfunction of osteoclast in Nf1 heterozygote is related with autocrine osteopontin,inhibition of OPN may be an effective treatment for bone destruction of neurofibromatosis type 1.%目的 研究体外培养的Nf1+/-小鼠破骨细胞合成、分泌骨桥蛋白(osteopontin,OPN)的能力,应用OPN中和抗体抑制破骨细胞分泌的OPN,测

  1. Multiple, Unilateral Lisch Nodules in the Absence of Other Manifestations of Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    E. G. Adams

    2011-01-01

    Full Text Available Lisch nodules associated with Neurofibromatosis Type 1 (NF1 are usually multiple and bilateral in nature. Here, we report a 21-year-old healthy, Caucasian female who was diagnosed with multiple, unilateral Lisch nodules during routine eye examination. A thorough history and physical examination revealed no other signs of NF1. We diagnosed the rare occurrence of numerous, unilateral Lisch nodules in the absence of additional features of NF1 in our patient and provide a discussion concerning the differential diagnosis of Lisch nodules as well as the potential genetic explanation of this finding.

  2. Huge Intrathoracic Malignant Peripheral Nerve Sheath Tumor in an Adolescent with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Jong Hyung Yoon

    2014-01-01

    Full Text Available Malignant peripheral nerve sheath tumor (MPNST is a rare soft tissue malignancy usually found in patients with neurofibromatosis type 1 (NF1 with a poor outcome. Although MPNST can be found in any part of the body including head and neck or extremities, intrathoracic MPNST with or without NF1 is uncommon, especially in children or adolescents. Reported herein is a case of huge intrathoracic MPNST in a 16-year-old girl with NF1, and a brief review of the literature.

  3. Spinal neurofibromatosis with central nervous system involvement in a set of twin girls and a boy: further expansion of the phenotype.

    Science.gov (United States)

    Ruggieri, Martino; Polizzi, Agata; Salpietro, Vincenzo; Incorpora, Gemma; Nicita, Francesco; Pavone, Piero; Falsaperla, Raffaele; Nucifora, Caterina; Granata, Francesca; Distefano, Angela; Padua, Luca; Caltabiano, Rosario; Lanzafame, Salvatore; Gabriele, Anna Lia; Ortensi, Andrea; D'Orazi, Valerio; Panunzi, Andrea; Milone, Pietro; Mankad, Kshitij; Platania, Nunzio; Albanese, Vincenzo; Pavone, Vito

    2013-10-01

    Familial spinal neurofibromatosis is a form of neurofibromatosis 1 (NF1), consisting of extensive, symmetrical, histologically proven, multiple neurofibromas of the spinal roots at every level and of all major peripheral nerves sometimes associated with typical NF1 stigmata; most cases underlie NF1 gene mutations. The objectives of this study are (1) to report the findings in a set of 16-year-old monozygotic twin girls and a 14-year-old boy and (2) to review the existing literature. In this article, we report the cases of three children who (1) had manifested mildly different symptomatic neuropathy (twins, aged 4 years; and a boy, aged 9 years) associated with massive, symmetrical neurofibromas; (2) had few café-au-lait spots with irregular margins and pale brown pigmentation; (3) were presented with, at brain magnetic resonance imaging (MRI), bilateral, NF1-like high-signal abnormalities in the basal ganglia; (4) yielded missense NF1 gene mutations in exon 39; and (5) had unaffected parents with negative NF1 genetic testing as well as discuss 12 families and 20 sporadic and 5 additional cases that presented spinal neurofibromatosis within classical NF1 families (53 cases) that were reported in the literature. This article presents the first report on (1) spinal neurofibromatosis in a set of affected monozygotic twins; (2) the earliest onset of the disease; and (3) the occurrence of high signal lesions in the brain at MRI. Georg Thieme Verlag KG Stuttgart · New York.

  4. Ⅰ型神经纤维瘤病中血管病变的研究进展%Research Progress of Vascular Abnormalities in NF1

    Institute of Scientific and Technical Information of China (English)

    高阳(综述); 胡晓洁; 林晓曦(审校)

    2014-01-01

    Ⅰ型神经纤维瘤病是一种常见的常染色体显性遗传病,主要由NF1基因突变导致。临床表现包括皮肤色斑和良性神经纤维瘤,病变可累及神经、骨骼、血管等多种组织结构。血管病变是NF1的常见并发症,患病率和死亡率较高。本文针对NF1中血管性病变的研究进展进行综述。%Neurofibromatosis type 1 is a common autosomal dominant condition caused by heterozygous mutations of the NF1 gene. The most frequent clinical manifestations are alterations of skin pigmentation and benign neurofibromas, but patients with NF1 may also develop nervous system tumors, skeletal abnormalities, or vascular disease. Vascular abnormalities is a common complication of NF1 and may lead to a high morbidity and mortality. The new findings of vascular abnormalities NF1were reviewed in this paper.

  5. Goblet cell carcinoid in a patient with neurofibromatosis type 1-a rare combination

    DEFF Research Database (Denmark)

    Gregersen, Tine; Holt, Nanna; Gronbaek, Henning

    2012-01-01

    Neuroendocrine tumors are rare tumors primarily located in the gastrointestinal tract. Goblet cell carcinoid is a rare subgroup of neuroendocrine tumors located in the appendix. Neurofibromatosis type 1 is an autosomal dominant disorder caused by a mutation in the NF1 gene. Patients...

  6. Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1

    NARCIS (Netherlands)

    M.H. Cnossen (Marjon); E.N. Stam (Esther N.); L.C.M.G. Cooiman (Linda C. M. G.); H.J. Simonsz (Huib); H. Stroink (Hans); A.P. Oranje (Arnold); D. Halley (Dicky); A. de Goede-Bolder (Arja); M.F. Niermeijer (Martinus); S.M.P.F. de Muinck Keizer-Schrama (Sabine)

    1997-01-01

    textabstractObjective. To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. Design. A prospective follow-up study. Setting. A multidisciplinary

  7. Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1

    NARCIS (Netherlands)

    M.H. Cnossen (Marjon); E.N. Stam (Esther N.); L.C.M.G. Cooiman (Linda C. M. G.); H.J. Simonsz (Huib); H. Stroink (Hans); A.P. Oranje (Arnold); D. Halley (Dicky); A. de Goede-Bolder (Arja); M.F. Niermeijer (Martinus); S.M.P.F. de Muinck Keizer-Schrama (Sabine)

    1997-01-01

    textabstractObjective. To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. Design. A prospective follow-up study. Setting. A multidisciplinary ne

  8. Neurofibromatosis type 1 associated with vertebrobasilar dolichoectasia and pontine ischemic stroke.

    Science.gov (United States)

    Giannantoni, Nadia Mariagrazia; Broccolini, Aldobrando; Frisullo, Giovanni; Pilato, Fabio; Profice, Paolo; Morosetti, Roberta; Di Lella, Giuseppe; Zampino, Giuseppe; Della Marca, Giacomo

    2015-01-01

    Neurofibromatosis type 1 (NF1) is a heterogeneous, common, neurocutaneous disorder presenting different complications during a life span, including cerebrovascular dysplasia. To our knowledge this is the first reported case of NF1 associated with vertebrobasilar dolichoectasia and pontine ischemic stroke. We describe a 57-year-old man with NF1 who presented an acute onset right-sided facial palsy and hemiplegia, dysarthria, and gait imbalance. Magnetic resonance imaging showed an acute left paramedian pontine infarct and a hypoplastic right vertebral artery. Brain Computed Tomography Angiography revealed the occurrence of vertebrobasilar dolichoectasia. Co-occurrence of VBD and NF1 might not be merely casual and it may significantly heighten the mortality rate in this multisystem disorder. We suggest a possible role of VBD in the genesis of our patient's clinical-radiological features and prompt the early detection of asymptomatic arteriopathy in individuals with NF1 in order to ameliorate patients' quality of life and life expectancy.

  9. Neurocognitive profiles of learning disabled children with neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Miladys eOrraca-Castillo

    2014-06-01

    Full Text Available Neurofibromatosis 1 (NF1 is a genetic condition generally associated with intellectual deficiency and learning disabilities. Although there have been groundbreaking advances in the understanding of the molecular, cellular, and neural systems underlying learning deficits associated to NF1 in animal models, much remains to be learned about the spectrum of neurocognitive phenotype associated with the NF1 clinical syndrome. In the present study, 32 children with NF1 ranging from 7 to 14 years were evaluated with neurocognitive tests dedicated to assess basic capacities which are involved in reading and mathematical achievement. Deficits in lexical and phonological strategies and poor number facts retrieval were found underlying reading and arithmetic disorders, respectively. Additionally, efficiencies in lexical/phonological strategies and mental arithmetic were significant predictors of individual differences in reading attainment and math. However, deficits in core numeric capacities were not found in the sample, suggesting that it is not responsible for calculation dysfluency. The estimated prevalence of Developmental Dyscalculia was 18.8%, and the male:female ratio was 5:1. On the other hand, the prevalence of Developmental Dyslexia was almost 3 times as high (50%, and no gender differences were found (male:female ratio=1:1. This study offers new evidence to the neurocognitive phenotype of NF1 contributing to an in depth understanding of this condition, but also to possible treatments for the cognitive deficits associated with NF1.

  10. Valuing gene testing in children with possible neurofibromatosis 1.

    Science.gov (United States)

    Tsang, E; Birch, P; Friedman, J M

    2012-12-01

    With the growing number of clinical guidelines recommending genetics tests in routine clinical care, the value of these tests should be evaluated. We examined the economic value of offering genetic testing to children with possible neurofibromatosis 1 (NF1) in British Columbia. Diagnosis of NF1 is usually made based on diagnostic clinical criteria, but molecular diagnostic testing, currently offered on a case-by-case basis in BC, now reliably diagnoses NF1 in 95% of cases. Children who present with some clinical features but whose findings are insufficient to meet the diagnostic criteria are labelled as having 'possible NF1'. Current guidelines call for these children to be followed as they have NF1, leading to annual ophthalmologic examinations and screening for complications; thus, there are increased costs to health care system. We created a model to account for these costs to the health care system, comparing the current protocol with one that would offer all children diagnosed with possible NF1 with genetic testing. Focusing on the incremental cost allowed us to determine that genetic testing provides good value, and patient interviews provided insight into the qualitative benefits of an earlier firm diagnosis. These findings may be helpful in guiding health policy decision-making.

  11. Neurofibromatosis tipo I con manifestaciones en el periodonto y lengua: presentación de un caso Type I neurofibromatosis with periodontal and lingual manifestations: a case report

    Directory of Open Access Journals (Sweden)

    M.C. Negreiros Lyrio

    2008-06-01

    Full Text Available La enfermedad de Von Recklinghausen o Neurofibromatosis Tipo I (NF1 es una condición autosómica dominante que presenta una variada expresión clínica, con manifestaciones que van desde manchas tipo café con leche en piel a severas complicaciones estéticas y funcionales afectando los tejidos óseos y nerviosos. Las manifestaciones orales de la NF1 son comunes, afectando aproximadamente al 72% de los pacientes. Presentamos un caso de NF1 con lesiones neurofibromatosas afectando al reborde alveolar inferior y lengua, con indicación de excisión quirúrgica debido a la dificultad de higiene local.Von Recklinghausen’s disease, or type I neurofibromatosis (NF-1, is an autosomal dominant condition with a varied clinical expression. Disease manifestations may range from café au lait spots of the skin to severe cosmetic and functional complications that affect bone and nervous tissues. Oral manifestations of NF-1 are common, affecting approximately 72% of patients. We report a case of NF-1 with neurofibromatous lesions of the lower alveolar bridge and tongue. Resection was indicated due to the difficulty of maintaining oral hygiene.

  12. Proteomic Analyses of NF1-Interacting Proteins in Keratinocytes

    Science.gov (United States)

    2015-04-01

    AWARD NUMBER: W81XWH-14-1-0070 TITLE: Proteomic Analyses of NF1 -Interacting Proteins in Keratinocytes PRINCIPAL INVESTIGATOR: Shyni Varghese...TITLE AND SUBTITLE 5a.CONTRACT NUMBER Proteomic Analyses of NF1 -Interacting Proteins in Keratinocytes 5b. GRANT NUMBER W81XWH-14-1-0070 5c. PROGRAM...in the NF1 null epidermis, we analyzed NF1 expression in a mouse model of psoriasis (imiquimod-induced psoriasis-like skin inflammation) and

  13. Adaptive Behavior in Young Children with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Bonita P. Klein-Tasman

    2013-01-01

    Full Text Available Neurofibromatosis-1 is the most common single gene disorder affecting 1 in 3000. In children, it is associated not only with physical features but also with attention and learning problems. Research has identified a downward shift in intellectual functioning as well, but to date, there are no published studies about the everyday adaptive behavior of children with NF1. In this study, parental reports of adaptive behavior of 61 children with NF1 ages 3 through 8 were compared to an unaffected contrast group (n=55 that comprised siblings and community members. Significant group differences in adaptive skills were evident and were largely related to group differences in intellectual functioning. In a subsample of children with average-range intellectual functioning, group differences in parent-reported motor skills were apparent even after controlling statistically for group differences in intellectual functioning. The implications of the findings for the care of children with NF1 are discussed.

  14. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning.

    Science.gov (United States)

    Anastasaki, Corina; Woo, Albert S; Messiaen, Ludwine M; Gutmann, David H

    2015-06-15

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Facial plexiform neurofibromatosis: A surgical challenge

    Directory of Open Access Journals (Sweden)

    Bharat B Dogra

    2013-01-01

    Full Text Available Plexiform neurofibromatosis is a relatively common but potentially devastating manifestation of neurofibromatosis type 1 (NF1. It produces very hideous deformity if the face is involved. Surgical management remains the mainstay of therapy, but in the head and neck region it is limited by the infiltrating nature of these tumors, inherent operative morbidity and high rate of regrowth. We present two cases of facial neurofibromatosis managed in our hospital. The first patient presented with overhanging mass of skin folds on the right side of her face, completely obliterating her right eye. The other patient was a young male having a huge, unsightly swelling over the right cheek, resulting in pulled down right eyelids and right pinna. Physical examination revealed the presence of café au lait macules, freckling in the axillary region and multiple neurofibromas over the trunk. Reconstructive surgical procedure in the form of subtotal excision of tumor mass followed by re draping of the facial skin was performed in both cases. There was evidence of regrowth of the tumor on review after 6 months.

  16. Lethal presentation of neurofibromatosis and Noonan syndrome.

    Science.gov (United States)

    Prada, Carlos E; Zarate, Yuri A; Hagenbuch, Sean; Lovell, Anne; Schorry, Elizabeth K; Hopkin, Robert J

    2011-06-01

    Neurofibromatosis type 1 and Noonan syndrome are both common genetic disorders with autosomal dominant inheritance. Similarities between neurofibromatosis type 1 and Noonan syndrome have been noted for over 20 years and patients who share symptoms of both conditions are often given the diagnosis of neurofibromatosis-Noonan syndrome (NFNS). The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades until the discovery that the syndromes are related through disturbances of the Ras pathway. We present an infant male with coarse facial features, severe supravalvar pulmonic stenosis, automated atrial tachycardia, hypertrophic cardiomyopathy, airway compression, severe neurological involvement, and multiple complications that lead to death during early infancy. The severity of clinical presentation and significant dysmorphic features suggested the possibility of a double genetic disorder in the Ras pathway instead of NFNS. Molecular analysis showed a missense mutation in exon 25 of the NF1 gene (4288A>G, p.N1430D) and a pathogenic mutation on exon 8 (922A>G, p.N308D) of the PTPN11 gene. Cardiovascular disease has been well described in patients with Noonan syndrome with PTPN11 mutations but the role of haploinsufficiency for neurofibromin in the heart development and function is not yet well understood. Our case suggests that a double genetic defect resulting in the hypersignaling of the Ras pathway may lead to complex cardiovascular abnormalities, cardiomyopathy, refractory arrhythmia, severe neurological phenotype, and early death. Copyright © 2011 Wiley-Liss, Inc.

  17. Optic pathway glioma associated with orbital rhabdomyosarcoma and bilateral optic nerve sheath dural ectasia in a child with neurofibromatosis-1

    Energy Technology Data Exchange (ETDEWEB)

    Nikas, Ioannis; Theofanopoulou, Maria; Lampropoulou, Penelope; Hadjigeorgi, Christiana [Aghia Sophia Children' s Hospital, Imaging Department, Athens (Greece); Pourtsidis, Apostolos; Kosmidis, Helen [Children' s Hospital, A. Kyriakou, Department of Oncology, Athens (Greece)

    2006-11-15

    Neurofibromatosis-1 (NF-1) is a multisystem disorder presenting with a variety of clinical and imaging manifestations. Neural and non-neural tumours, and unusual benign miscellaneous conditions, separately or combined, are encountered in variable locations. We present a 21/2-year-old boy with NF-1 who demonstrated coexisting optic pathway glioma with involvement of the chiasm and optic nerve, orbital alveolar rhabdomyosarcoma and bilateral optic nerve sheath dural ectasia. (orig.)

  18. Diagnosi molecolare della Distrofia Muscolare di Duchenne e della Neurofibromatosi tipo 1 con la tecnologia di sequenziamento Next Generation

    OpenAIRE

    Chessa, Roberta

    2014-01-01

    Duchenne/Becker muscular dystrophies (DMD/BMD) are the most frequent inherited neuromuscular diseases caused by mutations in the dystrophin gene (DMD). Neurofibromatosis type 1 (NF1), caused by mutations in the neurofibromin gene (NF1), is a multisystem genetic disorder that commonly is associated with cutaneous, neurologic, and orthopedic manifestations. Full characterisation of the mutational spectrum is necessary for genetic counselling, prenatal diagnosis and selecting the patients eligib...

  19. Generation of KCL025 research grade human embryonic stem cell line carrying a mutation in NF1 gene

    Directory of Open Access Journals (Sweden)

    Heema Hewitson

    2016-03-01

    Full Text Available The KCL025 human embryonic stem cell line was derived from an embryo donated for research that carried an autosomal dominant mutation in the NF1 gene encoding neurofibromin (c.3739–3742 ΔTTTG. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The ICM was isolated using laser microsurgery and plated on γ-irradiated human foreskin fibroblasts. Both the derivation and cell line propagation were performed in an animal product-free environment. Pluripotent state and differentiation potential were confirmed by in vitro assays.

  20. Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency.

    Science.gov (United States)

    Sachs, Zohar; Been, Raha A; DeCoursin, Krista J; Nguyen, Hanh T; Mohd Hassan, Nurul A; Noble-Orcutt, Klara E; Eckfeldt, Craig E; Pomeroy, Emily J; Diaz-Flores, Ernesto; Geurts, Jennifer L; Diers, Miechaleen D; Hasz, Diane E; Morgan, Kelly J; MacMillan, Margaret L; Shannon, Kevin M; Largaespada, David A; Wiesner, Stephen M

    2016-10-01

    Juvenile myelomonocytic leukemia is a rare myeloproliferative neoplasm characterized by hyperactive RAS signaling. Neurofibromin1 (encoded by the NF1 gene) is a negative regulator of RAS activation. Patients with neurofibromatosis type 1 harbor loss-of-function mutations in NF1 and have a 200- to 500-fold increased risk of juvenile myelomonocytic leukemia. Leukemia cells from patients with juvenile myelomonocytic leukemia display hypersensitivity to certain cytokines, such as granulocyte-macrophage colony-stimulating factor. The granulocyte-macrophage colony-stimulating factor receptor utilizes pre-associated JAK2 to initiate signals after ligand binding. JAK2 subsequently activates STAT5, among other downstream effectors. Although STAT5 is gaining recognition as an important mediator of growth factor signaling in myeloid leukemias, the contribution of STAT5 to the development of hyperactive RAS-initiated myeloproliferative disease has not been well described. In this study, we investigated the consequence of STAT5 attenuation via genetic and pharmacological approaches in Nf1-deficient murine models of juvenile myelomonocytic leukemia. We found that homozygous Stat5 deficiency extended the lifespan of Nf1-deficient mice and eliminated the development of myeloproliferative neoplasm associated with Nf1 gene loss. Likewise, we found that JAK inhibition with ruxolitinib attenuated myeloproliferative neoplasm in Nf1-deficient mice. Finally, we found that primary cells from a patient with KRAS-mutant juvenile myelomonocytic leukemia displayed reduced colony formation in response to JAK2 inhibition. Our findings establish a central role for STAT5 activation in the pathogenesis of juvenile myelomonocytic leukemia and suggest that targeting this pathway may be of clinical utility in these patients.

  1. Rupture of the Left External Iliac Artery and Right Groin Pseudoaneurysm Formation following Angioplasty in a Patient with Neurofibromatosis Type 1 and Undiagnosed Bilateral Phaeochromocytoma

    Directory of Open Access Journals (Sweden)

    Brett Doleman

    2013-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a genetic condition, which affects 1 in every 3000 births. Patients with NF1 are at increased risk of a variety of vascular abnormalities. This report presents the case of a 60-year-old male with NF1 who suffered a left external iliac rupture and a right pseudoaneurysm following angioplasty. In addition, these were further complicated by previously undiagnosed, bilateral phaeochromocytomas. The inherent weakness in vessel wall architecture found in NF1 coupled with the hypertension evident during and after the procedure contributed to haemorrhage and pseudoaneurysm formation. Caution must be taken in such patients when considering vascular intervention.

  2. Epithelioid hemangioendothelioma and multiple thoraco-lumbar lateral meningoceles: two rare pathological entities in a patient with NF-1

    Energy Technology Data Exchange (ETDEWEB)

    Reis, C.; Carneiro, E.; Fonseca, J.; Salgado, A. [Hospital S. Joao, Departments of Neuroradiology, Porto (Portugal); Pereira, P.; Vaz, R. [Hospital S. Joao, Department of Neurosurgery, Porto (Portugal); Pinto, R. [Hospital S. Joao, Department of Orthopaedics, Porto (Portugal); Capelinha, A.F.; Lopes, J.M. [Hospital S. Joao, Department of Pathology, Porto (Portugal)

    2005-02-01

    Epithelioid hemangioendothelioma (EHE) is a rare vascular soft-tissue tumour of intermediate malignancy. Neurofibromatosis type I (NF-1) is a genetic syndrome associated with soft tissue sarcoma and higher risk of developing neoplasia. Lateral meningoceles are uncommon entities, being mostly associated with NF-1. We report a case of a 31-year-old woman, with NF-1 and past history of right thalamic/peduncular astrocytoma WHO grade II, admitted to the Neurosurgery Department in December 2003 due to severe low back pain, irradiating to the left leg without a radicular pattern. Thoraco-lumbar magnetic resonance imaging (MRI) showed a large left posterior paravertebral expansive lesion, bilateral and multiple thoraco-lumbar lateral meningoceles and dural ectasias with scalloping of the vertebral bodies. Biopsy of the paravertebral mass lesion disclosed EHE. We present this case because of the novel association between NF-1 and EHE, and the unusual aggressiveness of the neoplasia. Additionally, we highlight the co-existence of bilateral and multiple lateral meningoceles. (orig.)

  3. An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation.

    Science.gov (United States)

    Perrin, George Q; Li, Hua; Fishbein, Lauren; Thomson, Susanne A; Hwang, Min S; Scarborough, Mark T; Yachnis, Anthony T; Wallace, Margaret R; Mareci, Thomas H; Muir, David

    2007-11-01

    Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth.

  4. Nf1 Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature

    Directory of Open Access Journals (Sweden)

    Debra A. Mayes

    2013-09-01

    Full Text Available Patients with neurofibromatosis type 1 (NF1 and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB developed, implicating a soluble mediator. Nitric oxide (NO can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3 were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.

  5. Imaging of Various Aspects of Neurofibromatosis Involvement: Case Series

    Directory of Open Access Journals (Sweden)

    Nazila Tayari

    2010-05-01

    Full Text Available Neurofibromatosis (NF is often noticed at birth or soon after. NF is divided into two types: NF type 1 is a complex of cutaneous and deep neural tumors. It is an autosomal dominant familial disorder. CNS is affected in about 15% of the cases. Optic nerve gliomas have a high degree of association with NF 1."nNF type 2 is much less commonly seen. It is also inherited as an autosomal dominant trait. Bilateral acoustic neuromas are pathognomonic of NF 2 and may be associated with meningiomas or ependymo-mas."nTypical clinical manifestations of neurofibromatosis are cafe-au-lait spots and multiple cutaneous tumors. There are also bone involvement as scoliosis, pseudoarthrosis of long bones, scalloping of vertebral bodies, abnormal rib tubulation, and defective ossification of the posterior superior wall of the orbit."nExtraskeletal manifestations of neurofibromatosis include gliomas of the optic nerves, pheochromocytoma, aneurysms of cerebral and renal arteries, acoustic neurilemmoma and superficial skin nodular neurofibromas."nHere, we intend to present images of several cases of neurofibromatosis with different aspects of involvement of the body. "nKeywords: Neurofibromatosis, Glioma, Schwannoma, Neurinoma

  6. High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

    Science.gov (United States)

    Rojnueangnit, Kitiwan; Xie, Jing; Gomes, Alicia; Sharp, Angela; Callens, Tom; Chen, Yunjia; Liu, Ying; Cochran, Meagan; Abbott, Mary-Alice; Atkin, Joan; Babovic-Vuksanovic, Dusica; Barnett, Christopher P; Crenshaw, Melissa; Bartholomew, Dennis W; Basel, Lina; Bellus, Gary; Ben-Shachar, Shay; Bialer, Martin G; Bick, David; Blumberg, Bruce; Cortes, Fanny; David, Karen L; Destree, Anne; Duat-Rodriguez, Anna; Earl, Dawn; Escobar, Luis; Eswara, Marthanda; Ezquieta, Begona; Frayling, Ian M; Frydman, Moshe; Gardner, Kathy; Gripp, Karen W; Hernández-Chico, Concepcion; Heyrman, Kurt; Ibrahim, Jennifer; Janssens, Sandra; Keena, Beth A; Llano-Rivas, Isabel; Leppig, Kathy; McDonald, Marie; Misra, Vinod K; Mulbury, Jennifer; Narayanan, Vinodh; Orenstein, Naama; Galvin-Parton, Patricia; Pedro, Helio; Pivnick, Eniko K; Powell, Cynthia M; Randolph, Linda; Raskin, Salmo; Rosell, Jordi; Rubin, Karol; Seashore, Margretta; Schaaf, Christian P; Scheuerle, Angela; Schultz, Meredith; Schorry, Elizabeth; Schnur, Rhonda; Siqveland, Elizabeth; Tkachuk, Amanda; Tonsgard, James; Upadhyaya, Meena; Verma, Ishwar C; Wallace, Stephanie; Williams, Charles; Zackai, Elaine; Zonana, Jonathan; Lazaro, Conxi; Claes, Kathleen; Korf, Bruce; Martin, Yolanda; Legius, Eric; Messiaen, Ludwine

    2015-11-01

    Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.

  7. Oncogene Mutation Survey in MPNST Cell Lines Enhances the Dominant Role of Hyperactive Ras in NF1 Associated Pro-Survival and Malignancy.

    Science.gov (United States)

    Sun, Daochun; Tainsky, Michael A; Haddad, Ramsi

    2012-01-01

    Malignant peripheral nerve sheath tumors (MPNST) are a type of soft tissue sarcoma that can be associated with germline mutations in Neurofibromatosis type 1 (NF1) or may occur sporadically. Although the etiology of MPNST is poorly understood, it is clear that a loss of function of the NF1 gene, encoding a Ras-GAP, is an important factor in the tumorigenesis of the inherited form of MPNST. Tumor latency in NF1 patients suggests that additional mutational events are probably required for malignancy. In order to define oncogene mutations associated with 5 MPNST cell lines, we assayed the 238 most frequent mutations in 19 commonly activated oncogenes using mass spectroscopy-based analysis. All 238 mutation sites in the assayed oncogenes were determined to harbor only wild-type sequences. These data suggest that hyperactive Ras resulting from the loss function of neurofibromin may be sufficient to set up the direction of malignant transformation of Schwann cells to MPNST.

  8. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas.

    Science.gov (United States)

    Vizcaíno, M Adelita; Shah, Smit; Eberhart, Charles G; Rodriguez, Fausto J

    2015-09-01

    Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration.

  9. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas☆

    Science.gov (United States)

    Vizcaíno, M. Adelita; Shah, Smit; Eberhart, Charles G.; Rodriguez, Fausto J.

    2015-01-01

    Summary Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration. PMID:26190195

  10. Orbitotemporal neurofibromatosis: classification and treatment.

    Science.gov (United States)

    Erb, Melanie H; Uzcategui, Nicolas; See, Robert F; Burnstine, Michael A

    2007-12-01

    To review the clinical findings in orbitotemporal neurofibromatosis and discuss treatment options. Clinical features, histopathologic characteristics, and treatment options are reviewed. A Medline literature search from 1966 to 2004 was performed, using the key words: orbitotemporal neurofibromatosis, orbitopalpebral neurofibromatosis, orbitofacial neurofibromatosis, cranio-orbital neurofibromatosis, and cranio-orbital-temporal neurofibromatosis, and the pertinent literature was reviewed. Additionally, our experience with two patients is reported. The surgical procedures are discussed. The management of orbitotemporal neurofibromatosis is challenging. The planned surgical approach and extent of resection depend on the severity of the orbital soft tissue and bony involvement and on the visual potential. Ultimately, orbital exenteration may be needed for rehabilitation and cosmesis.

  11. Evaluation of intratumoural heterogeneity on {sup 18}F-FDG PET/CT for characterization of peripheral nerve sheath tumours in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Salamon, Johannes; Derlin, Thorsten; Bannas, Peter; Busch, Jasmin D.; Herrmann, Jochen; Adam, Gerhard [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Bockhorn, Maximilian [University Medical Center Hamburg-Eppendorf, Department of General, Visceral and Thoracic Surgery, Hamburg (Germany); Hagel, Christian [University Medical Center Hamburg-Eppendorf, Institute of Neuropathology, Hamburg (Germany); Friedrich, Reinhard E. [University Medical Center Hamburg-Eppendorf, Department of Oral and Maxillofacial Surgery, Hamburg (Germany); Mautner, Victor F. [University Medical Center Hamburg-Eppendorf, Department of Neurology, Hamburg (Germany)

    2013-05-15

    The aim of the study was to evaluate the potential usefulness of intratumoural tracer uptake heterogeneity on {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT as compared to a cut-off maximum standardized uptake value (SUV{sub max}) for characterization of peripheral nerve sheath tumours (PNSTs) in neurofibromatosis type 1 (NF1). Fifty patients suffering from NF1 were examined by {sup 18}F-FDG PET/CT. Intralesional tracer uptake was analysed qualitatively and semi-quantitatively by measuring the mean and maximum SUV. Uptake heterogeneity was graded qualitatively using a three-point scale and semi-quantitatively by calculating an SUV-based heterogeneity index (HI{sub SUV}). Cohen's {kappa} was used to determine inter- and intra-rater agreement. Histopathological evaluation and clinical as well as radiological follow-up examinations served as the reference standards. A highly significant correlation between the degree of intratumoural uptake heterogeneity on {sup 18}F-FDG PET and malignant transformation of PNSTs was observed (p < 0.0001). Semi-quantitative HI{sub SUV} was significantly higher in malignant PNSTs (MPNSTs) than in benign tumours (p = 0.0002). Both intralesional heterogeneity and SUV{sub max} could be used to identify malignant tumours with a sensitivity of 100 %. Cohen's {kappa} was 0.86 for inter-rater agreement and 0.88 for intra-rater agreement on heterogeneity. MPNSTs in patients with NF1 demonstrate considerable intratumoural uptake heterogeneity on {sup 18}F-FDG PET/CT. Assessment of tumour heterogeneity is highly reproducible. Both tumour heterogeneity and a cut-off SUV{sub max} may be used to sensitively identify malignant PNSTs, but the specificity is higher for the latter. A combination of both methods leads to a non-significant improvement in diagnostic performance. (orig.)

  12. Evaluation of skin viscoelasticity in type 1 neurofibromatosis patients.

    Science.gov (United States)

    Mimoun, N; Razzouq, N; Wolkenstein, P; Moreno, J C; Marty, J P; Lantieri, L; Astier, A; Paul, M

    2006-01-01

    Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disease characterized by cutaneous benign tumors called neurofibromas. Surgery takes an important place in managing these skin disorders. However, skin distensibility and softness of NF1 patients quickly offset the surgical benefit. The aim of this study was to determine the rheological behavior of neurofibromas and compare it with healthy skin in an attempt to comprehend what leads to this phenomenon. Thirty patients were admitted to this study. A group of 24 healthy control subjects was also included. The skin elasticity was assessed by a noninvasive in vivo suction device (Cutometer) including 5 consecutive suctions. The assessments were performed on neurofibroma skin, the supposedly healthy skin around neurofibromas and the healthy skin of control subjects. The extensibility at the first and the fifth traction in NF1 patients (neurofibromas and the supposedly healthy skin around it) was significantly different compared to the healthy skin of control subjects. The viscoelastic parameters obtained from the neurofibromas were significantly different in comparison to those obtained from the supposedly healthy skin of NF1 patients and the healthy skin of control subjects. The rheological profiles of the neurofibromas and the apparent healthy skin of NF1 patients demonstrated a hyperextensibility behavior, but in neurofibromas, the skin was unable to return to its initial position at the end of the stretch.

  13. Facial emotion recognition, face scan paths, and face perception in children with neurofibromatosis type 1.

    Science.gov (United States)

    Lewis, Amelia K; Porter, Melanie A; Williams, Tracey A; Bzishvili, Samantha; North, Kathryn N; Payne, Jonathan M

    2017-05-01

    This study aimed to investigate face scan paths and face perception abilities in children with Neurofibromatosis Type 1 (NF1) and how these might relate to emotion recognition abilities in this population. The authors investigated facial emotion recognition, face scan paths, and face perception in 29 children with NF1 compared to 29 chronological age-matched typically developing controls. Correlations between facial emotion recognition, face scan paths, and face perception in children with NF1 were examined. Children with NF1 displayed significantly poorer recognition of fearful expressions compared to controls, as well as a nonsignificant trend toward poorer recognition of anger. Although there was no significant difference between groups in time spent viewing individual core facial features (eyes, nose, mouth, and nonfeature regions), children with NF1 spent significantly less time than controls viewing the face as a whole. Children with NF1 also displayed significantly poorer face perception abilities than typically developing controls. Facial emotion recognition deficits were not significantly associated with aberrant face scan paths or face perception abilities in the NF1 group. These results suggest that impairments in the perception, identification, and interpretation of information from faces are important aspects of the social-cognitive phenotype of NF1. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  14. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Lopes Ferraz Filho, Jose R.; Pontes Munis, Marcos; Soares Souza, Antonio; Sanches, Rafael A. [Medical School in Sao Jose do Rio Preto, Imaging Department, Sao Jose do Rio Preto, Sao Paulo (Brazil); Goloni-Bertollo, Eni M.; Pavarino-Bertelli, Erika C. [Center of Research and Attendance in Neurofibromatosis, Sao Paulo (Brazil)

    2008-03-15

    Lesions of the brain denominated as unidentified bright objects (UBOs), which are not included in the diagnostic criteria for neurofibromatosis type 1 (NF1) established by the National Institutes of Health (NIH), have been detected by MRI. The purpose of this study was to investigate the possibility of including the presence of UBOs as a diagnostic criterion for NF1 in children. The study included 88 children between the ages of 2 and 18 years. The case group consisted of 40 children diagnosed with sporadic or familial NF1 according to the criteria established by the NIH. A control group consisted of 48 individuals referred for routine MRI of the brain for other complaints not related to NF1. UBOs were identified in 70% of the NF1 patients and in none of the control group. The sensitivity of the presence of UBOs for the diagnosis of NF1 was 70% (CI 53-83%), with a false-negative rate of 30% (CI 27-47%), a specificity of 100% (CI 86-100%) and a false-positive rate of 0% (CI 0-14%). Faced with the difficulties in diagnosing NF1 in children and the high frequency and specificity of the presence UBOs identified by MRI in our series, we recommend the inclusion of the presence UBOs as a diagnostic criterion for NF1 in children. (orig.)

  15. NF1的发病机制及相关进展

    Institute of Scientific and Technical Information of China (English)

    胡小刚; 袁湘斌; 江华; 章建林

    2008-01-01

    1型神经纤维瘤病(neurofibromatosis type 1,NF1)是整形外科常见的皮肤肿瘤疾病,于1893年,由VonR ecldinghau sen首次报道,是最常见的常染色体显性遗传病之一,在全世界的发生率约为1:3500。NF1的临床表现多种多样,以皮肤咖啡斑、多发性神经纤维瘤为主要特征,可累及皮肤、骨骼、血管、周围神经和中枢神经等多个系统,常伴有智力障碍和发育不良。患者有肿瘤易患体质,可同时出现多种肿瘤,并有10%的发病率,发展成恶性周围神经鞘瘤(malignant pefipheral nerve sheath rumors,MPNSTs)。

  16. Body composition in adults with neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    MARCIO SOUZA

    Full Text Available SUMMARY Objective To evaluate the body composition and nutritional status of neurofibromatosis type 1 (NF1 adult patients. Method A cross-sectional study of 60 NF1 patients (29 men, 31 women aged ≥ 18 years who were evaluated from September 2012 to September 2013 in a Neurofibromatosis Outpatient Reference Center. Patients underwent nutritional assessment including measurements of weight, stature, waist circumference (WC, upper-arm circumference (UAC, and skinfolds (biceps, triceps, subscapular, suprailiac. Body mass index (BMI, upper-arm total area (UATA, upper-arm muscle area (UAMA, upper-arm fat area (UAFA, body fat percentage (BFP, fat mass, fat-free mass, fat mass index, and fat-free mass index were also calculated. Results The mean age of the study population was 34.48±10.33 years. The prevalence of short stature was 28.3%. Low weight was present in 10% of the sample and 31.7% of patients had a BMI ≥ 25 kg/m2. Reduced UAMA (<5th percentile was present in 43.3% and no difference was found in UAFA between the sexes. The BFP was considered high in 30% and 17 (28.3% patients had a WC above the World Health Organization cutoffs. Conclusion In this study, NF1 patients had a high prevalence of underweight, short stature, and reduced UAMA, with no difference between the sexes. Reduced UAMA was more prevalent in underweight patients; however, this was also observed in the normal and overweight patients. Further studies should investigate the distribution of body tissues in NF1 patients, including differences between men and women, and the influence of diet and nutrition on clinical features in NF1.

  17. The Role of NF1 in Memory Retrieval

    Science.gov (United States)

    2014-09-01

    AD_________________ Award Number: W81XWH-10-1-0450 TITLE: T R NF1 M PRINCIPAL... NF1 M R 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER YI ZHONG 5e. TASK NUMBER E-Mail: zhongyi...ABSTRACT This
three‐year
grant
supports
our
efforts
in
studying
a
role
of
the
neurofibromatosis
type
 1
( NF1 )
gene
in
mediating
retrieval
of
long‐term

  18. Nerve Degeneration and Regeneration Associated with NF1 Tumors

    Science.gov (United States)

    2014-09-01

    Associated with NF1 Tumors PRINCIPAL INVESTIGATOR: David F. Muir CONTRACTING ORGANIZATION: University of Florida...NUMBER Nerve Degeneration and Regeneration Associated with NF1 Tumors 5b. GRANT NUMBER W81XWH-11-1-0145 5c...for  the   eradication  of  PNSTs.    Our  preliminary  studies  indicate  that  PDT  effectively  kills  human   NF1

  19. Elucidating distinct roles for NF1 in melanomagenesis.

    Science.gov (United States)

    Maertens, Ophélia; Johnson, Bryan; Hollstein, Pablo; Frederick, Dennie T; Cooper, Zachary A; Messiaen, Ludwine; Bronson, Roderick T; McMahon, Martin; Granter, Scott; Flaherty, Keith; Wargo, Jennifer A; Marais, Richard; Cichowski, Karen

    2013-03-01

    BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways. As such, Nf1/Braf-mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase and mTOR. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and show that NF1/neurofibromin inactivation may have an impact on responses to targeted therapies.

  20. Feocromocitoma-ganglioneuroma compuesto en paciente con neurofibromatosis tipo 1

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    MARÍA VICENTE SANTOS

    2015-12-01

    Neurofibromatosis type 1 (NF-1 or Von Recklinhousen´s disease is a multisystem disease of autosomal dominant inheritance that primarily affects the skin and nervous system. Diagnosis is clinical and can be confirmed by genetic testing, but technically complex and does not predict the occurrence of complications, so it is not indicated routinely perform it. Neurofibromatosis type 1 is associated with various endocrine diseases, one of which pheochromocytoma. The compounds pheochromocytomas are rare tumors have also been associated with this syndrome. Pheochromocytomas associated with tumors with the same embryonic origin, associating ganglioneuromas being the most frequent. The prevalence of pheochromocytoma and ganglioneuroma may be increased in patients with NF-1 and this association has been associated with more aggressive tumors, so in this article stresses the importance of evaluating these patients to avoid complications related to the tumor early diagnosis is if it does. We report the case of a pheochromocytoma compound in an asymptomatic patient ganglioneuroma affect NF-1 and the most relevant aspects of this tumor are reviewed.

  1. Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation

    DEFF Research Database (Denmark)

    Nielsen, G P; Stemmer-Rachamimov, A O; Ino, Y

    1999-01-01

    Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We...

  2. A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Garza, Rene [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Hudson, Robert A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); McMahan, C. Alex [Department of Pathology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); Walter, Christi A. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States); South Texas Veterans Healthcare System, San Antonio, TX 78229 (United States); Vogel, Kristine S. [Department of Cellular and Structural Biology, University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900 (United States)]. E-mail: vogelk@uthscsa.edu

    2007-02-03

    Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF = 4.70) when compared to normal peripheral nerve and brain (MF = 2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.

  3. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

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    David F Wozniak

    Full Text Available Children with neurofibromatosis type 1 (NF1 frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice. In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at

  4. Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1

    Directory of Open Access Journals (Sweden)

    Mahija Janardhanan

    2011-01-01

    Full Text Available Neurofibromatosis-1 (NF-1 is a relatively common autosomal dominant disease characterized by multiple cutaneous fibromatoses and café au lait spots. It is associated with the mutation of NF-1 gene, a tumor suppressor gene located on chromosome 17q11.2. Hence, it can be considered as a familial cancer predisposition syndrome in which the affected individuals are at increased risk of developing malignancies. Intraoral neurofibromas associated with NF-1 are quite common, but the occurrence of malignant peripheral nerve sheath tumor (MPNST in the oral cavity is very rare. Oral MPNST can occur either de novo or by malignant transformation of neurofibromas or very rarely can represent a metastatic lesion. Here, we present a case of MPNST involving the maxillary region, in a patient with NF-1. Since MPNST often creates a diagnostic dilemma, histopathologic criteria for the diagnosis of MPNST are also discussed.

  5. Moyamoya syndrome associated with neurofibromatosis type I in a pediatric patient

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    Luiz Guilherme Darrigo Júnior

    Full Text Available CONTEXT: Neurofibromatosis type 1 (NF-1 is the most prevalent autosomal dominant genetic disorder among humans. Moyamoya disease is a cerebral vasculopathy that is only rarely observed in association with NF-1, particularly in the pediatric age range. The present study reports an occurrence of this association in an infant. CASE REPORT: An eight-month-old female presented convulsive seizures with clonic movements. The patient suffered an ischemic stroke with hemiparesis. Magnetic resonance imaging revealed radiological findings compatible with moyamoya disease. The diagnosis of NF-1 was made at the age of 20 months. CONCLUSION: Despite the rarity of this association in childhood, children with focal neurological symptoms and a diagnosis of NF-1 deserve to be investigated for moyamoya syndrome.

  6. Neurofibromatosis 1 vasculopathy manifesting as a peripheral aneurysm in an adolescent

    Energy Technology Data Exchange (ETDEWEB)

    Farmakis, Shannon G.; Khanna, Geetika [Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO (United States); Han, Min; White, Frances [Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, MO (United States)

    2014-10-15

    Arterial vasculopathy is a well-recognized but uncommon manifestation of neurofibromatosis type 1 (NF-1). It can manifest as stenoses, aneurysms or arteriovenous malformations. NF-1 vasculopathy typically involves the aorta, visceral arteries or carotid-vertebral circulation. Aortic and visceral vasculopathy typically presents as stenotic lesions, while aneurysms have been reported primarily in the subclavian/vertebral arteries. Aneurysms of the peripheral/extremity arteries are an extremely rare complication of NF-1 that may present as a mass or spontaneous rupture. We present the case of a teenage boy with an arm mass secondary to an aneurysm. We hope this case will increase recognition of the variable clinical manifestations of NF-1 vasculopathy among radiologists. (orig.)

  7. Physical, Cognitive, and Psychosocial Predictors of Functional Disability and Health-Related Quality of Life in Adolescents with Neurofibromatosis-1

    Directory of Open Access Journals (Sweden)

    Molly M. Garwood

    2012-01-01

    Full Text Available Objective. To examine physical, cognitive, and social-emotional predictors of quality of life (HRQOL and functional disability (FD in adolescents diagnosed with Neurofibromatosis-1. Methods. Participants were twenty-seven adolescents with a diagnosis of NF-1 who were recruited through an NF-1 specialty clinic at a large Midwestern children’s hospital. Measurements of the adolescents’ cognitive functioning, pain, FD, HRQOL, and social and emotional functioning were obtained with corresponding parent measures. Results. Emotional functioning significantly predicted youth-reported and parent-reported HRQOL, whereas days of pain significantly predicted youth-reported FD. Conclusions. NF-1 is a complex disease. Measurements of the overall impact of the disease tap into different aspects of the effects of NF-1 on daily life. Global outcomes such as HRQOL appear to be influenced especially by emotional functioning, whereas outcomes such as FD appear to be influenced by the physical/organic aspects of NF-1.

  8. Functional Analysis of Mutations in Exon 9 of NF1 Reveals the Presence of Several Elements Regulating Splicing.

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    Elisabete Hernández-Imaz

    Full Text Available Neurofibromatosis type 1 (NF1 is one of the most common human hereditary disorders, predisposing individuals to the development of benign and malignant tumors in the nervous system, as well as other clinical manifestations. NF1 is caused by heterozygous mutations in the NF1 gene and around 25% of the pathogenic changes affect pre-mRNA splicing. Since the molecular mechanisms affected by these mutations are poorly understood, we have analyzed the splicing mutations identified in exon 9 of NF1, which is particularly prone to such changes, to better define the possible splicing regulatory elements. Using a minigene approach, we studied the effect of five splicing mutations in this exon described in patients. These highlighted three regulatory motifs within the exon. An in vivo splicing analysis of an extensive collection of changes generated in the minigene demonstrated that the CG motif at c.910-911 is critical for the recognition of exon 9. We also found that the GC motif at c.945-946 is involved in exon recognition through SRSF2 and that this motif is part of a Composite Exon Splicing Regulatory Element made up of physically overlapping enhancer and silencer elements. Finally, through an in vivo splicing analysis and in vitro binding assays, we demonstrated that the c.1007G>A mutation creates an Exonic Splicing Silencer element that binds the hnRNPA1 protein. The complexity of the splicing regulatory elements present in exon 9 is most likely responsible for the fact that mutations in this region represent 25% of all exonic changes that affect splicing in the NF1 gene.

  9. NF1 regulation of RAS/ERK signaling is required for appropriate granule neuron progenitor expansion and migration in cerebellar development.

    Science.gov (United States)

    Sanchez-Ortiz, Efrain; Cho, Woosung; Nazarenko, Inga; Mo, Wei; Chen, Jian; Parada, Luis F

    2014-11-01

    Cerebellar development is regulated by a coordinated spatiotemporal interplay between granule neuron progenitors (GNPs), Purkinje neurons, and glia. Abnormal development can trigger motor deficits, and more recent data indicate important roles in aspects of memory, behavior, and autism spectrum disorders (ASDs). Germline mutation in the NF1 tumor suppressor gene underlies Neurofibromatosis type 1, a complex disease that enhances susceptibility to certain cancers and neurological disorders, including intellectual deficits and ASD. The NF1 gene encodes for neurofibromin, a RAS GTPase-activating protein, and thus negatively regulates the RAS signaling pathway. Here, using mouse models to direct conditional NF1 ablation in either embryonic cerebellar progenitors or neonatal GNPs, we show that neurofibromin is required for appropriate development of cerebellar folia layering and structure. Remarkably, neonatal administration of inhibitors of the ERK pathway reversed the morphological defects. Thus, our findings establish a critical cell-autonomous role for the NF1-RAS-ERK pathway in the appropriate regulation of cerebellar development and provide a basis for using neonatal ERK inhibitor-based therapies to treat NF1-induced cerebellar disorders.

  10. 1型神经纤维瘤病的基因学研究进展%The advanced genomics research of neurofibromatosis type 1

    Institute of Scientific and Technical Information of China (English)

    柯屹峰; 郝瑞; 张虹

    2010-01-01

    Neurofibromatosis type 1 is a term of Von Recklinghausenan.It is an autosomal dominant inherited disease which derived by neural crest cell.Prevalence of this disease is 1/3000 1/3500 and is a disease with the highest mutation rate.The pathogenesis of neurofibromatosis type 1 is associated with the deficiency of NF1 gene.Recently,the genetics and genomics research of neurofibromatosis make a great progress.With the development of gene linkage and position cloning technology,the gene sequence of neurofibromatosis type 1 has been found.Recent research of genetics and genomics of NF1 and the structure and function,abnormal expression,the relation of genotype and phenotype,the mutation sensitivity domain of NF1 gene were reviewed.%1型神经纤维瘤病(NF1)又称为Von Recklinghausen病,为起源于神经嵴细胞分化异常而导致多系统损害的一种常染色体显性遗传病,患病率为1/3000~1/3500,其发病与NF1基因的缺失有关.近年来对NF遗传和基因学的研究取得了很大进展,通过基因连锁和"定点克隆"技术获得了该病基因序列、突变及其表达信息.对近年在NF1基因和遗传学方面的研究成果、NF1基因的结构和功能、NF1基因的异常表达、该病基因型和表现性的关系、基因的易突变区域等进行综述.

  11. Multiple gastrointestinal stromal tumors and bilateral pheochromocytoma in neurofibromatosis

    Institute of Scientific and Technical Information of China (English)

    Klaus Kramer; Cornelia Hasel; Andrik J Aschoff; Doris Henne-Bruns; Peter Wuerl

    2007-01-01

    The coincidence of a gastrointestinal stromal tumor (GIST) and a neuroendocrine tumor (NET) in neurofibromatosis type 1 (NF1) is described only five times within the literature. We report on a 63 year old Caucasian female with the rare condition of neurofibromatosis type 1 coinciding with recurrent gastrointestinal stromal tumor plus bilateral pheochromocytoma (PCC). After a history of palpitations and dizziness that lasted for years, a left adrenal mass was detected by CT. Laparotomy revealed a pheochromocytoma of the left adrenal gland while an ileoterminal GIST was found incidentally intraoperatively.After six months contralateral PCC and multiple recurrent GIST were resected again. After four years the patient is doing well without any signs of further recurrent tumors.Discussion includes review of the literature.

  12. [Continuous clinical management of patients with neurofibromatosis type 1].

    Science.gov (United States)

    Ohno, Kousaku

    2010-01-01

    Neurofibromatosis type 1(NF1) is an autosomal dominant disorder with variable expression. The complications are age specific. Serious complication during early childhood is rare but optic glioma, brain tumors or leukemia may appear. Learning difficulties and attention deficit hyperactive disorders occur in as many as 60% of patients during school age. Overall, intelligence in neurofibromatosis is normal and mental retardation occurs in 6-7%. Managements for learning difficulties and attention deficit hyperactive disorders are especially important for quality of life in these patients. Skin neurofibromas or subcutaneous plexiform neurofibromas appear during childhood and may cause pain or spinal cord involvement. Malignant peripheral nerve sheath tumors that arise from plexiform neurifibromas are a particularly devastating complication during middle age.

  13. Mortality associated with neurofibromatosis type 1: A study based on Italian death certificates (1995-2006

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    Pace Monica

    2011-03-01

    Full Text Available Abstract Background Persons affected by neurofibromatosis type 1 (NF1 have a decreased survival, yet information on NF1-associated mortality is limited. Methods/Aim The National Mortality Database and individual Multiple-Causes-of-Death records were used to estimate NF1-associated mortality in Italy in the period 1995-2006, to compare the distribution of age at death (as a proxy of survival to that of the general population and to evaluate the relation between NF1 and other medical conditions by determining whether the distribution of underlying causes of NF1-associated deaths differs from that of general population. Results Of the nearly 6.75 million deaths in the study period, 632 had a diagnosis of NF1, yet for nearly three-fourths of them the underlying cause was not coded as neurofibromatosis. The age distribution showed that NF1-associated deaths also occurred among the elderly, though mortality in early ages was high. The mean age for NF1-associated death was approximately 20 years lower than that for the general population. The gender differential may suggest that women are affected by more severe NF1-related complications, or they may simply reflect a greater tendency for NF1 to be reported on the death certificates of young women. Regarding the relation with other medical conditions, we found an excess, as the underlying cause of death, for malignant neoplasm of connective and other soft tissue and brain, but not for other sites. We also found an excess for obstructive chronic bronchitis and musculoskeletal system diseases among elderly persons. Conclusion This is the first nationally representative population-based study on NF1-associated mortality in Italy. It stresses the importance of the Multiple-Causes-of-Death Database in providing a more complete picture of mortality for conditions that are frequently not recorded as the underlying cause of death, or to study complex chronic diseases or diseases that have no specific

  14. Brain Herniation in Neurofibromatosis with Dysplasia of Occipital Bone and Posterior Skull Base

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    Vithal Rangarajan

    2015-01-01

    Full Text Available A 22-year-old female, a known case of neurofibromatosis 1 (NF1, presented with a congenital swelling in the left occipital region. She had developed recent onset dysphagia and localized occipital headache. Neuroradiology revealed a left occipital meningoencephalocele and a left parapharyngeal meningocele. This was associated with ventriculomegaly. She was advised on cranioplasty along with duraplasty which she denied. She agreed to a lumbar-peritoneal shunt. She described a dramatic improvement in her symptoms following the lumbar-peritoneal shunt. Occipital dysplasias, though uncommon, have been reported in the literature. We review this case and its management and discuss relevant literature on occipital dysplasias in NF1.

  15. Pathological fracture dislocation of the acetabulum in a patient with neurofibromatosis-1

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    Balaji Saibaba

    2016-01-01

    Full Text Available Skeletal neurofibromatosis (NF commonly manifests as scoliosis and tibial dysplasias. NF affecting the pelvic girdle is extremely rare. Pathological fracture of the acetabulum leading to anterior hip dislocation in a patient with NF-1 has never been reported in the literature. The paper presents the clinical symptomatology, the course of management and the successful outcome of such a rare case of NF-1. Histopathological and immunohistochemistry studies showing abundant spindle cells, which are S-100 positive and of neural origin are the classical hallmarks of neurofibromatous lesions. Tumor resection and iliofemoral arthrodesis can be considered as a valid option in young patients with pathological fracture dislocation of the acetabulum.

  16. Intraosseous malignant peripheral nerve sheath tumor in a patient with neurofibromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Terry, D.G. [VA Medical Center, Imaging Service (114-P), 3710 S.W. US Veterans Hospital Road, Portland, OR 97201 (United States); Sauser, D.D. [Department of Radiology, Oregon Health Sciences University Portland, Oregon (United States); Gordon, M.D. [Department of Pathology, Oregon Health Sciences University, Portland, Oregon (United States)

    1998-06-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon sarcomas that almost always arise in soft tissue. They can develop in pre-existing neurofibromas or schwannomas, de novo from peripheral nerves, or following radiation therapy. Primary intraosseous MPNST is rare and has been reported most frequently in the mandible. Of the reported cases involving the long bones, none has been associated with neurofibromatosis type 1 (NF-1). We report a case of MPNST arising in the femur in a patient with NF-1. (orig.) With 2 figs., 2 tabs., 6 refs.

  17. Optical Coherence Tomography Imaging of Choroidal Abnormalities in Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Shinji Makino

    2013-01-01

    Full Text Available We report a case of neurofibromatosis type 1 (NF1 examined by infrared fundus autofluorescence (IR-FAF and optical coherence tomography (OCT to characterize the associated choroidal abnormalities. The conventional ophthalmoscopic findings were unremarkable. However, IR-FAF revealed multiple bright patchy lesions in the choroid of the posterior pole, in both eyes. OCT demonstrated irregular hyperreflectivity at the sites of these lesions. Patients with NF1 may have typical choroidal lesions that are visible on IR-FAF, which can be confirmed through OCT.

  18. Spontaneous Renal Artery Dissection in a Patient with Neurofibromatosis Type I

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    Nicolas W. Shammas

    2016-01-01

    Full Text Available We present a case of spontaneous renal artery dissection (SRAD in a 28-year-old female with history of neurofibromatosis type I (NF-1 treated successfully with endovascular stenting. The clinical presentation, diagnostic testing, and treatment options are discussed. An endovascular approach with stenting was successfully performed after failure of medical treatment with subcutaneous low molecular weight heparin. Patient’s blood pressure and symptoms improved significantly. This may be the first reported case of SRAD in a patient with NF-1 successfully treated with endovascular stenting.

  19. Neurofibromatosis type 1 and attention deficit hyperactivity disorder: a case study and literature review

    Directory of Open Access Journals (Sweden)

    Miguel CS

    2015-03-01

    Full Text Available Carmen Sílvia Miguel, Tiffany M Chaim-Avancini, Maria Aparecida Silva, Mario Rodrigues LouzãAdult Attention Deficit Hyperactivity Disorder Program (PRODATH, Institute of Psychiatry, University of São Paulo, São Paulo, BrazilBackground: The cognitive profile of children with neurofibromatosis type 1 (NF1 and attention deficit hyperactivity disorder (ADHD has been well characterized, but few studies have evaluated the cognitive abilities of adults with NF1 and ADHD.Objectives: We investigated 1 the cognitive profile of an adult patient with NF1 and inattention problems, 2 changes in his cognition after 14 months of follow-up, and 3 whether the patient exhibited comorbid NF1 and ADHD or secondary ADHD-like symptoms.Methods: We administered neuropsychological tests of executive function, attention, verbal and visual memory, visuospatial function, and language during two evaluations separated by 14 months.Results: We found no changes in sustained attention, language, or verbal memory. Visual memory, verbal learning, selective attention inhibitory control, and problem solving declined over time, whereas visual search, psychomotor speed, visuospatial function, and mental flexibility improved.Conclusion: Our patient exhibited a cognitive profile characteristic of both NF1 and ADHD, leading to the hypothesis that the patient had comorbid ADHD instead of secondary ADHD-like symptoms. More studies are necessary to characterize the cognition of patients with NF1 and ADHD.Keywords: ADHD, executive function, NF1, low-grade pontine glioma, cognition

  20. Response inhibition in Attention deficit disorder and neurofibromatosis type 1 – clinically similar, neurophysiologically different

    Science.gov (United States)

    Bluschke, Annet; von der Hagen, Maja; Papenhagen, Katharina; Roessner, Veit; Beste, Christian

    2017-01-01

    There are large overlaps in cognitive deficits occurring in attention deficit disorder (ADD) and neurodevelopmental disorders like neurofibromatosis type 1 (NF1). This overlap is mostly based on clinical measures and not on in-depth analyses of neuronal mechanisms. However, the consideration of such neuronal underpinnings is crucial when aiming to integrate measures that can lead to a better understanding of the underlying mechanisms. Inhibitory control deficits, for example, are a hallmark in ADD, but it is unclear how far there are similar deficits in NF1. We thus compared adolescent ADD and NF1 patients to healthy controls in a Go/Nogo task using behavioural and neurophysiological measures. Clinical measures of ADD-symptoms were not different between ADD and NF1. Only patients with ADD showed increased Nogo errors and reductions in components reflecting response inhibition (i.e. Nogo-P3). Early perceptual processes (P1) were changed in ADD and NF1. Clinically, patients with ADD and NF1 thus show strong similarities. This is not the case in regard to underlying cognitive control processes. This shows that in-depth analyses of neurophysiological processes are needed to determine whether the overlap between ADD and NF1 is as strong as assumed and to develop appropriate treatment strategies. PMID:28262833

  1. Overexpression of PDGFRA cooperates with loss of NF1 and p53 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors

    Science.gov (United States)

    Ki, D H; He, S; Rodig, S; Look, A T

    2017-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, frequently metastatic sarcomas that are associated with neurofibromatosis type 1 (NF1), a prominent inherited genetic disease in humans. Although loss of the NF1 gene predisposes to MPNST induction, relatively long tumor latency in NF1 patients suggests that additional genetic or epigenetic abnormalities are needed for the development of these nerve sheath malignancies. To study the molecular pathways contributing to the formation of MPNSTs in NF1 patients, we used a zebrafish tumor model defined by nf1 loss in a p53-deficient background together with the overexpression of either wild-type or constitutively activated PDGFRA (platelet-derived growth factor receptor-α) under control of the sox10 neural crest-specific promoter. Here we demonstrate the accelerated onset and increased penetrance of MPNST formation in fish overexpressing both the wild-type and the mutant PDGFRA transgenes in cells of neural crest origin. Interestingly, overexpression of the wild-type PDGFRA was even more potent in promoting transformation than the mutant PDGFRA, which is important because ~78% of human MPNSTs have expression of wild-type PDGFRA, whereas only 5% harbor activating mutations of the gene encoding this receptor. Further analysis revealed the induction of cellular senescence in zebrafish embryos overexpressing mutant, but not wild-type, PDGFRA, suggesting a mechanism through which the oncogenic activity of the mutant receptor is tempered by the activation of premature cellular senescence in an NF1-deficient background. Taken together, our study suggests a model in which overexpression of wild-type PDGFRA associated with NF1 deficiency leads to aberrant activation of downstream RAS signaling and thus contributes importantly to MPNST development—a prediction supported by the ability of the kinase inhibitor sunitinib alone and in combination with the MEK inhibitor trametinib to retard MPNST progression in

  2. Overexpression of PDGFRA cooperates with loss of NF1 and p53 to accelerate the molecular pathogenesis of malignant peripheral nerve sheath tumors.

    Science.gov (United States)

    Ki, D H; He, S; Rodig, S; Look, A T

    2017-02-23

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, frequently metastatic sarcomas that are associated with neurofibromatosis type 1 (NF1), a prominent inherited genetic disease in humans. Although loss of the NF1 gene predisposes to MPNST induction, relatively long tumor latency in NF1 patients suggests that additional genetic or epigenetic abnormalities are needed for the development of these nerve sheath malignancies. To study the molecular pathways contributing to the formation of MPNSTs in NF1 patients, we used a zebrafish tumor model defined by nf1 loss in a p53-deficient background together with the overexpression of either wild-type or constitutively activated PDGFRA (platelet-derived growth factor receptor-α) under control of the sox10 neural crest-specific promoter. Here we demonstrate the accelerated onset and increased penetrance of MPNST formation in fish overexpressing both the wild-type and the mutant PDGFRA transgenes in cells of neural crest origin. Interestingly, overexpression of the wild-type PDGFRA was even more potent in promoting transformation than the mutant PDGFRA, which is important because ~78% of human MPNSTs have expression of wild-type PDGFRA, whereas only 5% harbor activating mutations of the gene encoding this receptor. Further analysis revealed the induction of cellular senescence in zebrafish embryos overexpressing mutant, but not wild-type, PDGFRA, suggesting a mechanism through which the oncogenic activity of the mutant receptor is tempered by the activation of premature cellular senescence in an NF1-deficient background. Taken together, our study suggests a model in which overexpression of wild-type PDGFRA associated with NF1 deficiency leads to aberrant activation of downstream RAS signaling and thus contributes importantly to MPNST development-a prediction supported by the ability of the kinase inhibitor sunitinib alone and in combination with the MEK inhibitor trametinib to retard MPNST progression in

  3. A Rare Cause of Pheochromocytoma; Neurofibromatosis Type 1-Noonan Syndrome

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    Mazhar Müslüm Tuna

    2014-09-01

    Full Text Available Neurofibromatosis (NF Type 1 (NF-1 is an autosomal dominant disease with a prevalence of about 1/3000. NF-1 is a neurocutaneous syndrome characterized by cafe au lait macules, neurofibroma, optic glioma, lisch nodules, and symptoms involving other systems. Noonan syndrome (NS is a clinically heterogeneous disorder predominantly characterized by dysmorphic facial features, congenital heart disease, proportionate post-natal short stature, neck abnormalities, and chest deformities. NF-NS is a very rare overlapping syndrome sharing many features of both syndromes. Coexistence of pheochromocytoma, which can be life-threatening if not treated properly, is also a very rare complication of this disorder. Here, we report a patient who was admitted with a mass in the right upper quadrant and was diagnosed with pheochromocytoma and NFNS. (The Me­di­cal Bul­le­tin of Ha­se­ki 2014; 52: 227-31

  4. Gastrointestinal neurofibromatosis with malignant transformation: a case report

    Institute of Scientific and Technical Information of China (English)

    Fariba Binesh; Ali Akhavan; Saeed Arefanian; Manuchehr Haidari

    2013-01-01

    Neurofibromatosis type1 (NF1), also known as Von Recklinghausen's disease with approximate occurrence of 1/3000 births, can be considered as a common autosomal dominant condition. Abdominal organs can be involved as neurofibroma and tumor growth in the liver, mesentery, retroperitoneum, stomach and bowel. Association of NF and gastrointestinal peripheral nerve sheath tumor (MPNST), usually arising within a pre-existing plexiform neurofibroma which metastasizes widely heraldinga poor outcome. We report a 55 year old man with gastrointestinal NF which ultimately developed MPNST and deceased.

  5. Cutaneous Manifestations Of Neurofibromatosis Type 1 In South India

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    Jeevankumar B

    2001-01-01

    Full Text Available Neurofibromatosis type 1 (NF-1 is the most common form of neurofibromatosis. Since the significance of various cutaneous manifestations of NF-1 has not been known in Indian population, hence, the present study was undertaken. A total of 40 patients with NF-1 were identified between August 1998 to June 2000 with a prevalence rate of 20.4 per 10,000 individuals attending our clinic. Male to female ratio was 2.3: 1. The age of the patients ranged from 15 to 70 years with a mean age of 29.57 years. Most patients (18 cases belonged to age group of 21-30 years followed by 11-20 years age group (11 cases. Twenty four cases had onset of disease between 11-20 years of age and ten cases in 21-30 years age group. Thirty one of 40 cases presented with asymptomatic nodules, three sought medical opinion for cosmetic reasons and another three for hyper pigmented patch. Analysis of cutaneous manifestations showed, 39 of 40 cases (97.5% had neurofibromas. Palmar melanotic macules were noted in 36 (90% cases whereas café â€" au-lait macules were seen in 33(82.5% cases. Subsequent, less common findings were intertriginous freckles in 31(77.5% cases, plantar melanotic macules in 18(45% cases and generalized freckles in 4(10% cases. Statistical analysis of cases and controls revealed significant association of NF-1 with neurofibromas, palmar melanotic macules, café-au-lait macules, intertriginous freckles and plantar melanotic macules(p<0.001. This study brings into focus some of the cutaneous manifestations noted in South Indian patients especially palmar and plantar melanotic macules, not highlighted in the western literature.

  6. Neurofibromatosis type 2 appears to be a genetically homogeneous disease

    Energy Technology Data Exchange (ETDEWEB)

    Narod, S.A.; Parry, D.M.; Parboosingh, J.; Lenoir, G.M.; Ruttledge, M.; Fischer, G.; Eldridge, R.; Martuza, R.L.; Frontali, M.; Haines, J.; Gusella, J.F.; Rouleau, G.A.

    1992-09-01

    Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomos, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, where as the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, the authors have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. The results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. The authors believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in the families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution. 42 refs., 4 figs., 3 tabs.

  7. Genetic modifiers of neurofibromatosis type 1-associated cafe-au-lait macule count identified using multi-platform analysis.

    Directory of Open Access Journals (Sweden)

    Alexander Pemov

    2014-10-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161 between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6 was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

  8. Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

    Directory of Open Access Journals (Sweden)

    Alexander Pemov

    2014-10-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161 between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6 was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

  9. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features.

    Science.gov (United States)

    Ruggieri, M; Polizzi, A; Spalice, A; Salpietro, V; Caltabiano, R; D'Orazi, V; Pavone, P; Pirrone, C; Magro, G; Platania, N; Cavallaro, S; Muglia, M; Nicita, F

    2015-05-01

    Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4-74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non-SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café-au-lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14-13.11], which were more frequent in SNF vs MNFSR (p = 0.0271). © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

    Science.gov (United States)

    Pasmant, Eric; Parfait, Béatrice; Luscan, Armelle; Goussard, Philippe; Briand-Suleau, Audrey; Laurendeau, Ingrid; Fouveaut, Corinne; Leroy, Chrystel; Montadert, Annelore; Wolkenstein, Pierre; Vidaud, Michel; Vidaud, Dominique

    2015-05-01

    Molecular diagnosis of neurofibromatosis type 1 (NF1) is challenging owing to the large size of the tumour suppressor gene NF1, and the lack of mutation hotspots. A somatic alteration of the wild-type NF1 allele is observed in NF1-associated tumours. Genetic heterogeneity in NF1 was confirmed in patients with SPRED1 mutations. Here, we present a targeted next-generation sequencing (NGS) of NF1 and SPRED1 using a multiplex PCR approach (230 amplicons of ∼150 bp) on a PGM sequencer. The chip capacity allowed mixing 48 bar-coded samples in a 4-day workflow. We validated the NGS approach by retrospectively testing 30 NF1-mutated samples, and then prospectively analysed 279 patients in routine diagnosis. On average, 98.5% of all targeted bases were covered by at least 20X and 96% by at least 100X. An NF1 or SPRED1 alteration was found in 246/279 (88%) and 10/279 (4%) patients, respectively. Genotyping throughput was increased over 10 times, as compared with Sanger, with ∼90[euro ] for consumables per sample. Interestingly, our targeted NGS approach also provided quantitative information based on sequencing depth allowing identification of multiexons deletion or duplication. We then addressed the NF1 somatic mutation detection sensitivity in mosaic NF1 patients and tumours.

  11. Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

    Science.gov (United States)

    Pasmant, Eric; Parfait, Béatrice; Luscan, Armelle; Goussard, Philippe; Briand-Suleau, Audrey; Laurendeau, Ingrid; Fouveaut, Corinne; Leroy, Chrystel; Montadert, Annelore; Wolkenstein, Pierre; Vidaud, Michel; Vidaud, Dominique

    2015-01-01

    Molecular diagnosis of neurofibromatosis type 1 (NF1) is challenging owing to the large size of the tumour suppressor gene NF1, and the lack of mutation hotspots. A somatic alteration of the wild-type NF1 allele is observed in NF1-associated tumours. Genetic heterogeneity in NF1 was confirmed in patients with SPRED1 mutations. Here, we present a targeted next-generation sequencing (NGS) of NF1 and SPRED1 using a multiplex PCR approach (230 amplicons of ∼150 bp) on a PGM sequencer. The chip capacity allowed mixing 48 bar-coded samples in a 4-day workflow. We validated the NGS approach by retrospectively testing 30 NF1-mutated samples, and then prospectively analysed 279 patients in routine diagnosis. On average, 98.5% of all targeted bases were covered by at least 20X and 96% by at least 100X. An NF1 or SPRED1 alteration was found in 246/279 (88%) and 10/279 (4%) patients, respectively. Genotyping throughput was increased over 10 times, as compared with Sanger, with ∼90€ for consumables per sample. Interestingly, our targeted NGS approach also provided quantitative information based on sequencing depth allowing identification of multiexons deletion or duplication. We then addressed the NF1 somatic mutation detection sensitivity in mosaic NF1 patients and tumours. PMID:25074460

  12. Neurofibromatosis type 1 and attention deficit hyperactivity disorder: a case study and literature review

    OpenAIRE

    Miguel CS; Chaim-Avancini TM; Silva MA; Louzã MR

    2015-01-01

    Carmen Sílvia Miguel, Tiffany M Chaim-Avancini, Maria Aparecida Silva, Mario Rodrigues LouzãAdult Attention Deficit Hyperactivity Disorder Program (PRODATH), Institute of Psychiatry, University of São Paulo, São Paulo, BrazilBackground: The cognitive profile of children with neurofibromatosis type 1 (NF1) and attention deficit hyperactivity disorder (ADHD) has been well characterized, but few studies have evaluated the cognitive abilities o...

  13. Use of Balloon Enteroscopy in Preoperative Diagnosis of Neurofibromatosis-Associated Gastrointestinal Stromal Tumours of the Small Bowel: A Case Report

    Directory of Open Access Journals (Sweden)

    Kazuki Takakura

    2011-05-01

    Full Text Available Neurofibromatosis type I (NF1 is one of the most common inheritable disorders and is associated with an increased risk of gastrointestinal stromal tumours (GISTs. However, the predominant location of these lesions in the small bowel makes them difficult to diagnose. We report the successful use of balloon enteroscopy in conjunction with conventional methods for clinical diagnosis of jejunal GISTs in a 70-year-old man with NF1 who presented with melaena. The importance of screening NF1 patients for GISTs and the complementary role of balloon enteroscopy with capsule endoscopy in such diagnoses is discussed.

  14. Genetic Factors that Affect Tumorigenesis in NF1

    Science.gov (United States)

    2004-11-01

    Boles, R. and Korf, B. (1995) Sanitarias de la Seguridad Social (98-0992) and Institut Catali Deletion of the entire NFI gene detected by FISH: four...Washington, Medical Genetics, Seattle, WA, USA, 2Medical and Molecular Genetics Center- IRO, Hospital Duran i Reynals, Barcelona, Spain, 3Servizio di... Hospital . Western blot analysis, using an anti-NF1 antibody (NFIGRD(D)) (Santa Cruz Biotechnology Inc, Santa Cruz, NF1 mutation analysis CA) and

  15. High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1

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    Trovó-Marqui A.B.

    2005-01-01

    Full Text Available A clinical study of Brazilian patients with neurofibromatosis type 1 (NF1 was performed in a multidisciplinary Neurofibromatosis Program called CEPAN (Center of Research and Service in Neurofibromatosis. Among 55 patients (60% females, 40% males who met the NIH criteria for the diagnosis of NF1, 98% had more than six café-au-lait patches, 94.5% had axillary freckling, 45% had inguinal freckling, and 87.5% had Lisch nodules. Cutaneous neurofibromas were observed in 96%, and 40% presented plexiform neurofibromas. A positive family history of NF1 was found in 60%, and mental retardation occurred in 35%. Some degree of scoliosis was noted in 49%, 51% had macrocephaly, 40% had short stature, 76% had learning difficulties, and 2% had optic gliomas. Unexpectedly high frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis were observed, probably reflecting the detailed clinical analysis methods adopted by the Neurofibromatosis Program. These same patients were screened for mutations in the GAP-related domain/GRD (exons 20-27a by single-strand conformation polymorphism. Four different mutations (Q1189X, 3525-3526delAA, E1356G, c.4111-1G>A and four polymorphisms (c.3315-27G>A, V1146I, V1317A, c.4514+11C>G were identified. These data were recently published.

  16. The genetic and neuroanatomical basis of social dysfunction: lessons from neurofibromatosis type 1.

    Science.gov (United States)

    Pride, Natalie A; Korgaonkar, Mayuresh S; Barton, Belinda; Payne, Jonathan M; Vucic, Steve; North, Kathryn N

    2014-05-01

    Neurofibromatosis type 1 (NF1) is a common genetic condition associated with cognitive and social dysfunction as well as abnormal brain structure. The pathophysiology underlying social dysfunction in NF1 is poorly understood. Here, we investigate for the first time whether there is a broad deficit of social cognition in NF1 and explore the neural correlates for these deficits. Twenty-nine adults with NF1 and 30 controls were administered an ecologically based test of social cognition, The Awareness of Social Inference Test (TASIT), to identify deficits in emotion recognition and sarcasm detection. We employed voxel-based morphometry in a subset of NF1 patients (n = 16) and 16 additional controls to examine the neural correlates of these deficits. Results indicated that adults with NF1 were impaired in their ability to understand paradoxical sarcasm and their capacity to recognize emotion, particularly anger. TASIT performance was not associated with measures of attention, visuospatial skills or executive function. Relative to controls, gray matter (GM) volume within the right superior temporal gyrus (STG) was decreased, after controlling for total brain volume. Decreased volume in this region was significantly associated with social cognitive deficits in adults with NF1. We conclude that patients with NF1 are at high risk for a social cognitive deficit and provide evidence for a neuroanatomical basis for this deficit; GM volumetric reductions in the right STG. These findings improve our understanding of the nature of social interaction impairments in NF1 and add to the growing body of literature indicating the STG as a critical brain region for social cognition.

  17. Globus pallidus high-signal lesions: A predominant MRI finding in children with neurofibromatosis type 1

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    Arif Khan

    2013-01-01

    Full Text Available Introduction: Lesions of the brain, recognized as unidentified bright objects (UBOs, are commonly observed as areas of increased T2-weighted signal intensity on magnetic resonance imaging (MRI in children with neurofibromatosis type 1 (NF1. Identification of these lesions is not currently encompassed in the National Institute of Health (NIH diagnostic criteria for NF1. Objective: We aimed to determine the prevalence of UBOs in children with NF1 and identify areas of the brain that are commonly affected by these lesions, allowing us to evaluate whether UBOs should be included in the diagnostic criteria for the diagnosis of NF1. Materials and Methods: We reviewed the cranial MRI scans of 22 children who had been diagnosed with sporadic or familial NF1 in accordance with the criteria established by NIH. UBOs were present in 81% of the children with NF1. Results: These lesions have a predilection for specific areas of the brain, including the globus pallidus (72%, cerebellum (66%, brainstem (27% and cerebral hemispheres (16%. The prevalence of UBOs identified varied significantly with age and sex; they were infrequent in children less than 4 years of age but were common in those aged between 4 and 12 years of age. UBOs were more commonly seen in males (66.6% compared with females (33.3%. Repeat MRI scan on a subset of these patients with UBOs did not show any significant changes despite a worsening in clinical symptoms. Conclusion and Discussion: We have shown that UBOs are a common finding in children with NF1, and are most prevalent between the ages of 4 and 12 years. Many sites of the brain are affected by these lesions, most notably the globus pallidus and the cerebellum. Further research must be conducted to elucidate the significance of UBOs in patients with NF1 and whether these lesions have any utility in the clinical detection of NF1.

  18. Spatial working memory in neurofibromatosis 1: Altered neural activity and functional connectivity.

    Science.gov (United States)

    Ibrahim, Amira F A; Montojo, Caroline A; Haut, Kristen M; Karlsgodt, Katherine H; Hansen, Laura; Congdon, Eliza; Rosser, Tena; Bilder, Robert M; Silva, Alcino J; Bearden, Carrie E

    2017-01-01

    Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1. BOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM. Relative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls. Dysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task-negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.

  19. Monozygotic twins with Neurofibromatosis type 1, concordant phenotype and synchronous development of MPNST and metastasis

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    Melean German

    2010-08-01

    Full Text Available Abstract Background Neurofibromatosis type 1 is a common autosomal dominant disorder with full penetrance and variable expression. The condition predisposes individuals to the development of malignant nervous system tumours, most frequently Malignant Peripheral Nerve Sheath Tumours (MPNSTs. Previous studies indicate that genetic factors other than mutations in NF1 may be responsible for the condition's variable expression. Case report Here we present data from a pair of monozygotic twins affected by Neurofibromatosis type 1 resulting from a de novo mutation. Both twins developed a left sciatic plexiform neurofibroma that evolved into MPNST at a similar age and they also developed pulmonary metastasis at the same age. Other concordant traits between the twins were: macrocephaly, psychomotor delay, café-au-lait spots, cutaneous neurofibromas, retroperitoneal, pleural and paraspinal neurofibromas. The main discordant features observed were tibial pseudoarthrosis, pectus carinatum, osteoporosis and thymus hyperplasia. Conclusions This is the first report of monozygotic twins with Neurofibromatosis type 1 that develop MPNSTs, the localization and chronological evolution of which, and its metastasis, is concordant in both twins. These cases suggest that the events involved in the transformation of benign plexiform neurofibromas to MPNSTs in Neurofibromatosis type 1, follow a spatiotemporally programme that is influenced by heritable factors other than NF1 mutations.

  20. Radiologic findings in neurofibromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dai Young; Jeon, Seok Chol; Lee, Kwan Se; Yeon, Kyung Mo; Choo, Dong Woon [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1979-12-15

    Neurofibromatosis is an uncommon but certainly not a rare hereditary disorder, probably of neuralcrest origin, involving not only neuroectoderm and mesoderm but also endoderm and characterized by cafe au lait spots and cutaneous and subcutaneous tumors, with secondary mesodermal defects responsible for protean osseous abnormalities and various manifestations in other systems. This paper is a study of confirmed 143 cases of neurofibromatosis collected for past 8 years. In this analysis, special attention was given to the selected 37 cases which showed abnormal findings on radiological examinations. Overall male to female ratio was 1 : 1.3. The most frequent kind of abnormalities was vertebral kyphoscoliosis in 12 cases. Among the more pathognomonic but uncommon abnormalities to neurofibromatosis, we experienced each 2 cases of lambdoid defect, pseudoarthrosis and renovascular hypertension, and 1 cases of sphenoid bone absence.

  1. Gene Therapy for Childhood Neurofibromatosis

    Science.gov (United States)

    2014-05-01

    of cells heterozygous for the neurofibromin ( NF1 ) gene. Cells with two functional alleles of NF1 did not support tumor growth. The treatment...objective was therefore to increase the level of expression from the one active copy of NF1 to complement the haploinsufficiency in the cells of the tumor... NF1 ), artificial transcription factor, TALE DNA-binding protein, bacterial delivery vector 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  2. B lineage acute lymphoblastic leukemia transformation in a child with juvenile myelomonocytic leukemia, type 1 neurofibromatosis and monosomy of chromosome 7. Possible implications in the leukemogenesis

    DEFF Research Database (Denmark)

    Scrideli, Carlos Alberto; Baruffi, Marcelo Razera; Rogatto, Silvia Regina

    2003-01-01

    diagnosis of JMML and ALL, suggesting that both neoplasias may have evolved from the same clone. Our results support the theory that JMML may derive from pluripotential cells and that the occurrence of monosomy of chromosome 7 within a clone of cells having an aberrant neurofibromatosis type 1 (NF1) gene...

  3. Predicting neurofibromatosis type 1 risk among children with isolated café-au-lait macules.

    Science.gov (United States)

    Ben-Shachar, Shay; Dubov, Tom; Toledano-Alhadef, Hagit; Mashiah, Jacob; Sprecher, Eli; Constantini, Shlomi; Leshno, Moshe; Messiaen, Ludwine M

    2017-06-01

    Although isolated cafe-au-lait macules (CALMs) are a common skin finding, they are an early feature of neurofibromatosis type 1 (NF1). We sought to develop an algorithm determining the risk of children with CALMs to have constitutional NF1. We conducted a retrospective study of patients with isolated CALMs. Diagnosis of NF1 was based on detecting NF1 mutation in blood or fulfilling clinical criteria. In all, 170 of 419 (41%) and 21 of 86 (24%) children with isolated CALMs who underwent molecular testing and clinical follow-up, respectively, were given a diagnosis of NF1. Presence of fewer than 6 CALMs at presentation or atypical CALMs was associated with not having NF1 (P < .001). An algorithm based on age, CALMs number, and presence of atypical macules predicted NF1 in both cohorts. According to the algorithm, children older than 29 months with at least 1 atypical CALM or less than 6 CALMs have a 0.9% (95% confidence interval 0%-2.6%) risk for constitutional NF1 whereas children younger than 29 months with 6 or more CALMs have a high risk (80.4%, 95% confidence interval 74.6%-86.2%). The study was designed to detect constitutional NF1 and not NF1 in mosaic form. A simple algorithm enables categorization of children with isolated CALMs as being at low or high risk for having NF1. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  4. Seizure, spinal schwannoma, peripheral neuropathy and pulmonary stenosis - A rare combination in a patient of Neurofibromatosis 1

    Directory of Open Access Journals (Sweden)

    Avas Chandra Ray

    2012-01-01

    Full Text Available Neurofibromatosis 1 (NF1 is the most common neurocutaneous syndrome. It is estimated to occur in approximately 1 out of every 3300 infants. The manifestations of this condition are diverse and can arise from almost any system in the body. The neurofibroma is the hallmark lesion of NF1 that develops from peripheral nerves. Here, we are reporting an 18-year-old girl with NF1. Clinical diagnosis was made according to the diagnostic criteria established by the National Institutes of Health Consensus Development Conference in 1987. She presented with quadriparesis due to dumbbell-shaped spinal schwannoma in the cervical region. She had history of recurrent seizures in the past, with poor scholastic performance. There were clinical and electrophysiological features of peripheral neuropathy and clinical and echocardiographical features of pulmonary stenosis. These are uncommon features of NF 1. The presence of all these features in a single patient makes it a unique case.

  5. Glaucoma and globe enlargement associated with neurofibromatosis type 1.

    Science.gov (United States)

    Morales, Jose; Chaudhry, Imtiaz A; Bosley, Thomas M

    2009-09-01

    To describe the features of glaucoma and globe enlargement sometimes associated with neurofibromatosis type 1 (NF1). Single institution, retrospective, and cross-sectional study. Eighty medical records of patients treated at King Khaled Eye Specialist Hospital in Saudi Arabia with NF1 were reviewed, and 46 patients were examined. We reviewed the charts of patients with NF1 and examined available individuals, including gonioscopy, axial length, and ultrasound biomicroscopy in appropriate patients. Presence and type of glaucoma, anterior chamber angle abnormalities, globe axial length, ultrasound biomicroscopy, and visual outcome. Two patient groups were identified: Group 1 had 56 patients with orbito-facial NF1, and group 2 had 24 patients with NF1 but without orbito-facial involvement. Group 1 included 13 patients with glaucoma (23%), which occurred only ipsilateral to the orbito-facial involvement and generally presented before age 3 years. Glaucoma surgery was required in all of these patients, and visual prognosis was poor. In group 1, mean axial length on the side affected by NF1 was 29.8+/-4.1 mm in patients with glaucoma and 25.6+/-2.0 mm in patients without glaucoma. Patients with glaucoma (Pglobes on the affected side. Group 2 patients had a mean axial length of 23.6+/-1.6 mm for both eyes without significant globe asymmetry. In this Arab population, glaucoma associated with orbito-facial NF1 occurred less often than the 50% rate that is typically cited. Glaucoma presented early in life and only in patients with ipsilateral orbito-facial involvement. Glaucoma in this setting was always associated with globe enlargement. Glaucoma required surgery, and visual prognosis was poor because of glaucoma and concurrent pathology. Globe enlargement was most severe when associated with glaucoma but also present on the side with orbito-facial involvement in patients without glaucoma. The presence of neurofibroma may induce globe enlargement on the affected side in

  6. Pediatric neurofibromatosis 1 and parental stress: a multicenter study

    Directory of Open Access Journals (Sweden)

    Esposito M

    2014-01-01

    Full Text Available Maria Esposito,1 Rosa Marotta,2 Michele Roccella,3 Beatrice Gallai,4 Lucia Parisi,3 Serena Marianna Lavano,2 Marco Carotenuto1 1Clinic of Child and Adolescent Neuropsychiatry, Department of Mental Health, Physical and Preventive Medicine, Second University of Naples, Naples, Italy; 2Department of Psychiatry, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; 3Child Neuropsychiatry, Department of Psychology, University of Palermo, Palermo, Italy; 4Unit of Child and Adolescent Neuropsychiatry, University of Perugia, Perugia, Italy Background: Neurofibromatosis 1 (NF1 is a complex and multifaceted neurocutaneous syndrome with many and varied comorbidities. The literature about the prevalence and degree of maternal stress and the impact of NF1 in the parent–child interaction is still scant. The aim of this study was to evaluate the prevalence of maternal stress in a large pediatric sample of individuals affected by NF1. Methods: Thirty-seven children (19 boys, 18 girls of mean age 7.86±2.94 (range 5–11 years affected by typical NF1 and a control group comprising 405 typically developing children (207 boys, 198 girls; mean age 8.54±2.47 years were included in this study. To assess parental stress, the mothers of all individuals (NF1 and comparisons filled out the Parenting Stress Index-Short Form test. Results: The two study groups were comparable for age (P=0.116, gender (P=0.886, and body mass index adjusted for age (P=0.305. Mothers of children affected by NF1 reported higher mean Parenting Stress Index-Short Form scores on the Parental Distress domain (P<0.001, Difficult Child domain (P<0.001, and Total Stress domain than the mothers of typically developing children (controls (P<0.001. No significant differences between the two groups were found for the Parent-Child Dysfunctional Interaction domain (P=0.566 or Defensive Responding domain scores (P=0.160. Conclusion: NF1 is considered a multisystemic and complex disease, with many

  7. [Neurofibromatosis type 1. Splicing mutation detected by MLPA and DNA sequencing in Argentina].

    Science.gov (United States)

    Laurito, Sergio; Di Pierri, José; Roqué, María

    2015-01-01

    Neurofibromatosis type 1 (NF1) is a dominant autosomic genetic disorder, with a birth incidence of 1 in 2500-3000. Diagnosis is difficult because of the size of gene NF1 that has few hot-spots sites, the absence of a clear genotype-phenotype relation, and a heterogeneous clinical manifestation. A NF1 suspected case from Jujuy province was analyzed by multiplex ligation-dependent probe amplification (MLPA). Mestizo female teenage (Amerindian/European), with a maxilar osteoma, lumbar lordosis, cutaneous neurofibromas and café au lait spots. MLPA detected an alteration in exon 13 of the NF1 gene. By sequencing of exon 13, a missense mutation (NM_000267.3:c.1466A>G) was found which introduces an aberrant splicing site and is registered as pathogenic in the clinical variants database of NCBI. As far as we are aware, this is the first report of a NF1 mutation in mestizo population of Northwest Argentina. 1466A>G has been described before in patients of European origin, suggesting that the affected site could be a hot-spot site of the gene. For countries as Argentina, with limited availability of molecular diagnostic methods, we propose a diagnosis algorithm by starting the mutational analysis of NF1 with MLPA. This methodology is relatively simple and of low cost, avoiding to send samples abroad for genetic analyses.

  8. A Case of Persistent Foot Pain in a Neurofibromatosis Type I Patient

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    Vasilis Stavrinides

    2012-01-01

    Full Text Available Introduction. This is the case of a young male patient who presented to his family physician with atypical left foot pain, which was extremely resistant to analgesia and caused significant disability. Despite extensive investigations, the cause of his pain was not identified until 18 months after his initial symptoms, when the official diagnosis of malignant peripheral nerve sheath tumour (MPNST was made. Detailed review of the patient’s past history established the diagnosis of type I neurofibromatosis (NF-1, previously undetected. Discussion. NF-1 is an autosomal dominant genetic disorder caused by loss of function mutations of the NF1 gene in chromosome 17. Patients with this condition are at increased risk for developing MPNSTs which, however, are treatable only in early stages. Conclusion. Although monitoring NF-1 patients for the development of MPNSTs is common practice, the index of clinical suspicion in patients without an established NF-1 diagnosis is low. Any atypical pain in young adults should raise the possibility of this malignancy, and this case illustrates the fact that MPNSTs can be the first manifestation of NF-1 in patients previously undiagnosed with the disease.

  9. Diffusion tensor MR imaging in neurofibromatosis type 1: expanding the knowledge of microstructural brain abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Ferraz-Filho, Jose R.L.; Muniz, Marcos P.; Souza, Antonio S. [Medical School in Sao Jose do Rio Preto (FAMERP), Radiology Department, Sao Paulo (Brazil); Rocha, Antonio J. da [School Medical Sciences of the Santa Casa de Sao Paulo, Radiology Department, Sao Paulo (Brazil); Goloni-Bertollo, Eny M.; Pavarino-Bertelli, Erika C. [Center of Research and attendace in Neurofibromatosis (CEPAN) of Medical School in Sao Jose do Rio Preto (FAMERP), Sao Paulo (Brazil)

    2012-04-15

    Neurofibromatosis type 1 (NF1) is a hereditary disease with a dominant autosomal pattern. In children and adolescents, it is frequently associated with the appearance of T2-weighted hyperintensities in the brain's white matter. MRI with diffusion tensor imaging (DTI) is used to detect white matter abnormalities by measuring fractional anisotropy (FA). This study employed DTI to evaluate the relationship between FA patterns and the findings of T2 sequences, with the aim of improving our understanding of anatomical changes and microstructural brain abnormalities in individuals with NF1. Forty-four individuals with NF1 and 20 control subjects were evaluated. The comparative analysis of FA between NF1 and control groups was based on four predetermined anatomical regions of the brain hemispheres (basal ganglia, cerebellum, pons, thalamus) and related the presence or absence of T2-weighted hyperintensities in the brain, which are called unidentified bright objects (UBOs). The FA values between the groups demonstrated statistically significant differences (P {<=} 0.05) for the cerebellum and thalamus in patients with NF1, independent of the occurrence of UBOs. Diffusion tensor MR imaging confirms the influence of UBOs in the decrease of FA values in this series of patients with NF1. Additionally, this technique allows the characterization of microstructural abnormalities even in some brain regions that appear normal in conventional MR sequences. (orig.)

  10. Different Patterns of Mast Cells Distinguish Diffuse from Encapsulated Neurofibromas in Patients with Neurofibromatosis 1

    Science.gov (United States)

    Tucker, Tracy; Riccardi, Vincent M.; Sutcliffe, Margaret; Vielkind, Juergen; Wechsler, Janine; Wolkenstein, Pierre; Friedman, Jan M.

    2011-01-01

    Multiple neurofibromas are cardinal features of neurofibromatosis 1 (NF1). Several different types of NF1-associated neurofibromas occur, each distinct in terms of pathological details, clinical presentation, and natural history. Mast cells are present in most neurofibromas and have been shown to be critical to the origin and progression of neurofibromas in both human NF1 and relevant mouse models. In this investigation, the authors determined whether mast cell involvement is the same for all types of NF1-associated neurofibromas. They examined the density and distribution of mast cells within 49 NF1-associated neurofibromas classified histopathologically as diffuse or encapsulated on the basis of the presence or absence of the perineurium or its constituent cells. They made two observations: (1) Diffuse neurofibromas had significantly higher densities of mast cells than did encapsulated neurofibromas, and (2) mast cells were evenly distributed throughout diffuse neurofibromas but were primarily restricted to the periphery of encapsulated neurofibromas. The differences in mast cell density and distribution differentiate the two basic types of NF1-associated neurofibromas, suggesting that the pathogenesis of diffuse and encapsulated neurofibromas may be significantly different. PMID:21525187

  11. A Potential Role for Felbamate in TSC- and NF1-Related Epilepsy: A Case Report and Review of the Literature

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    Natanya M. Mishal

    2015-01-01

    Full Text Available A 15-year-old girl with maternal inheritance of neurofibromatosis type 1 (NF1 and paternal inheritance of tuberous sclerosis complex (TSC developed intractable epilepsy at age 5. Her seizures were refractory to adequate doses of four antiepileptic medications until felbamate was initiated at age 7. She has since remained seizure-free on felbamate monotherapy. Although felbamate has multiple mechanisms of action, it is thought to have its most potent antiepileptic effects through inhibition of the N-methyl-D-aspartate receptor (NMDAR. Previous studies have shown that the NMDAR is altered in varying epilepsy syndromes and notably in the cortical tubers found in TSC. The aim of this paper is to examine how felbamate monotherapy was able to achieve such robust antiepileptic effects in a unique patient and possibly offer a novel therapeutic approach to patients suffering from TSC- and NF-related epilepsy.

  12. BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through Bim Induction

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    Amish J. Patel

    2014-01-01

    Full Text Available Malignant peripheral nerve sheath tumors (MPNSTs are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 (NF1 patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized an MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of a chromatin regulator, Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.

  13. Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma

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    Cora Antoinette Ricker

    2016-12-01

    Full Text Available Neurofibromatosis type 1 (NF1 is an autosomal dominant disorder that results from germline mutations of the NF1 gene, creating a predisposition to low-grade gliomas (pilocytic astrocytoma; PA in young children. Insufficient data and resources represent major challenges to identifying the best possible drug therapies for children with this tumor. Herein, we summarize the currently-available cell lines, genetically-engineered mouse models, and therapeutic targets for these low-grade gliomas (LGGs. Conspicuously absent are human tumor-derived cell lines or patient-derived xenograft models for NF1-LGG. New collaborative initiatives between patients and their families, research groups and pharmaceutical companies are needed to create transformative resources and broaden the knowledge base relevant to identifying cooperating genetic drivers and possible drug therapeutics for this common pediatric brain tumor.

  14. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1

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    O'Sullivan Brendan

    2009-02-01

    Full Text Available Abstract Background Gastrointestinal stromal tumours (GIST frequently occur in patients with neurofibromatosis type 1 (NF-1. It has been reported that GIST may co-exist with pancreatic endocrine tumors but this has only been in association with NF-1. Case presentation A 76 year old woman presented with a 12 month history of hypoglycaemia symptoms. Abdominal CT scan demonstrated a 13 mm insulinoma localized in the tail of her pancreas. She was commenced on diazoxide and later underwent surgery for enucleation of insulinoma when a small ( Conclusion This is the first case report of a pancreatic insulinoma co-existing with a GIST in a patient without NF-1. In addition, we make the first report of rapidly growing cystic GIST recurrence following resection of a primary GIST tumour.

  15. Coexistence of Two Rare Genetic Disorders: Familial Mediterranean Fever and Neurofibromatosis Type 1 in A Child

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    Faruk incecik

    2015-03-01

    Full Text Available Familial Mediterranean fever (FMF is an autosomal recessive polysystemic disease characterized by attacks of relapsing and self-limiting fever, peritonitis, pleuritis and arthritis. Caf and eacute;-au lait macules, neurofibromas, axillary and inguinal freckling, Lisch nodules, bone lesions such as sphenoid dysplasia, and optic glioma are the characteristic features of neurofibromatosis type 1 (NF1 disease. In this case report, a 7 year-old girl with NF1 and FMF is presented. She had intermittent fever, abdominal and joint pain attacks lasting 2-3 days every two-three months since 1 year. We detected many cafe-au lait spots and axillary freckles on her body and diagnosed FMF and NF1. [Cukurova Med J 2015; 40(Suppl 1: 75-78

  16. Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer.

    Science.gov (United States)

    Wang, Xia; Teer, Jamie K; Tousignant, Renee N; Levin, Albert M; Boulware, David; Chitale, Dhananjay A; Shaw, Brandon M; Chen, Zhihua; Zhang, Yonghong; Blakeley, Jaishri O; Acosta, Maria T; Messiaen, Ludwine M; Korf, Bruce R; Tainsky, Michael A

    2017-09-10

    NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA-based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in-frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate-penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty-five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions. © 2017 Wiley Periodicals, Inc.

  17. Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature.

    Science.gov (United States)

    Vranceanu, Ana-Maria; Merker, Vanessa L; Park, Elyse; Plotkin, Scott R

    2013-09-01

    The aim of this study was to review the literature on quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis, and to identify the specific aspects of quality of life that were studied and reported in this population. We also set out to report predictors of quality of life. Published research reports were included if they described quality of life in this population and met methodological quality according to a list of predefined criteria. Eight studies (7 in NF1, 1 in NF2, 0 in schwannomatosis), conducted between 2001 and 2013, met inclusion criteria. The methodological quality of the eight studies was mostly high according to ratings by predefined criteria. Most studies reported that patients with NF experience decreased quality of life when compared to the general population. Visibility and disease severity were strong predictors of skin-specific quality of life in NF1 patients. However, the majority of findings regarding predictors of quality of life were weak or inconclusive. Given the decreased quality of life in NF patients, it is important to examine more comprehensively the psychosocial factors in this population, especially in patients with NF2 and schwannomatosis. Mind body interventions that address these domains may provide comprehensive and efficacious long term treatment.

  18. Neurofibromatosis type 1 and the "elephant man's" disease: the confusion persists: an ethnographic study.

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    Claire-Marie Legendre

    Full Text Available BACKGROUND: In 1986, two Canadian geneticists had demonstrated that Joseph Merrick, better known as the Elephant Man, suffered from the Proteus syndrome and not from neurofibromatosis type 1 (NF1, as was alleged by dermatologist Parkes in 1909. Despite this and although the two diseases differ at several levels: prevalence, diagnostic criteria, clinical manifestations and transmission, the confusion between NF1 and the "elephant man's" disease continues in medical and social representations by current linguistic usage, and in some media reports. With this article, we want to 1 document the persistence and extent of this fallacy, 2 identify certain critical factors that contribute to its persistence, and 3 evaluate its impact on the health and well being of patients with NF1 and their family members. METHODOLOGY: Participant observation in the course of an ethnographic study on intergenerational dialogue between individuals with neurofibromatosis and their parents - Analysis of the scientific literature and of pinpoint articles in the print and online news media. FINDINGS: Our findings show that because physicians have little knowledge about NF1, several print and online news media and a lot of physicians continue to make the confusion between NF1 and the disease the "elephant man". This misconception contributes to misinformation about the disease, feeding prejudices against affected patients, exacerbating the negative impacts of the disease on their quality of life, their cognitive development, their reproductive choices, as well as depriving them of proper care and appropriate genetic counseling. CONCLUSION: If family physicians and pediatricians were properly informed about the disease, they could refer their patients with NF1 to NF clinics and to specialists. Thus, patients and their family members would benefit from better-tailored clinical management of their cases, perhaps even optimal management. [corrected

  19. Reconstruction of the sphenoid wing in a case of neurofibromatosis type 1 and complex unilateral orbital dysplasia with pulsating exophthalmos.

    Science.gov (United States)

    Friedrich, Reinhard E

    2011-01-01

    Sphenoid wing dysplasia is a defining feature of neurofibromatosis type 1 (NF1). This defect of the skull base can be associated with pulsating exophthalmos. This report describes the successful reconstruction of a dysplastic sphenoid wing in an NF1 patient using lateral orbitotomy as a scarcely visible and sufficiently extendable approach. An intraoperative computed cone-beam computed tomography system (3D C-arm system) was used as a prompt and feasible technique to check the positioning of the titanium mesh in an anatomic region that is sensitive to mechanical stress.

  20. Functional Analysis of Human NF1 in Drosophia

    Science.gov (United States)

    2006-01-01

    Heefelfinger, S., Benvenuto , G., Ling, B., Li, S., Rui, W., Vass, W.C., Viskochil, D., and Ratner, N. (1992) Abnormal regulation of mammalian...and Cawthon, R. (1993) The neurofibromatosis type 1 gene. Annu. Rev. Neurosci., 16, 183–205. 15. DeClue, J.E., Heffelfinger, S., Benvenuto , G., Ling

  1. Uptake of health monitoring and disease self-management in Australian adults with neurofibromatosis type 1: strategies to improve care.

    Science.gov (United States)

    Crawford, H A; Barton, B; Wilson, M J; Berman, Y; McKelvey-Martin, V J; Morrison, P J; North, K N

    2016-03-01

    Lifelong health monitoring is recommended in neurofibromatosis type 1 (NF1) because of the progressive and unpredictable range of disabling and potentially life-threatening symptoms that arise. In Australia, strategies for NF1 health surveillance are less well developed for adults than they are for children, resulting in inequalities between pediatric and adult care. The aims of this study were to determine the uptake of health monitoring and capacity of adults with NF1 to self-manage their health. Australian adults with NF1 (n = 94, 18-40 years) participated in a semi-structured interview. Almost half reported no regular health monitoring. Thematic analysis of interviews identified four main themes as to why: (i) did not know where to seek care, (ii) unaware of the need for regular monitoring, (iii) futility of health monitoring as nothing can be done for NF1, and (iv) feeling healthy, therefore monitoring unnecessary. Overall, there were low levels of patient activation, indicating that adults with NF1 lacked knowledge and confidence to manage their health and health care. Findings are discussed in the context of service provision for adults with NF1 in New South Wales, Australia.

  2. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing

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    B. Quintáns

    2011-04-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a multisystem disease with autosomal dominant inheritance and complete penetrance diagnosed by clinical findings. Cutaneous neurofibromas are present in almost all adult patients in the dermis, epidermis or along the peripheral nerves. Plexiform neurofibromas are subcutaneous or deep lesions involving nerve plexuses or roots. Neurofibromas can degenerate into malignant tumors, with important prognostic implications. NF1 shows a broad clinic variability even within a single family. Exceptions are cases reporting the in-frame microdeletion c.2970_2972delAAT, presenting with the typical pigmentary features of NF1, but no cutaneous or plexiform neurofibromas. We report a patient with a de novo c.2970_2972delAAT mutation who had few café-au-lait spots, only 2 of which measured >15 mm, axillary and submammary freckling, a flat angioma extending over the neck, arm and trunk, a high arched palate, micrognathia, macrocephaly, pes cavus and scoliosis. There was complete absence of observable cutaneous neurofibromas as well as external plexiform neurofibromas. She had had epileptic seizures since childhood; however, a diagnosis of NF1 had not been confirmed until she was 38, partly due to the paucity of characteristic cutaneous stigmata. We confirm the association of the c.2970_2972delAAT mutation in NF1 with a particular clinical phenotype, especially with lack of detectable neurofibromas. For an appropriate management of patients and family counseling, molecular study of the NF1 gene should be considered in patients not fulfilling NIH criteria when other features suggestive of NF1 are present. In the absence of neurofibromas, starting NF1 testing with the screening of exon 17 may be worthwhile.

  3. Pheochromocytoma associated with neurofibromatosis type 1: concepts and current trends

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    Vogiaki Sophia

    2010-03-01

    Full Text Available Abstract Background Neurofibromatosis Type 1(NF-1 has autosomal dominant inheritance with complete penetrance, variable expression and a high rate of new mutation. Pheochromocytoma occurs in 0.1%-5.7% of patients with NF-1. Case presentation We present the case of a 37-year-old patient with laparoscopically resected pheochromocytoma. He was investigated for hypertension, flushing and ectopic heart beat. Abdominal CT and MRI revealed a mass measuring 8 × 4 cm in the right adrenal gland. The diagnosis of pheochromocytoma was confirmed by elevated 24-hour urine levels of VMA, metanephrines and catecholamines as well as positive MIBG scan. The patient presented with classic clinical features of NF-1, which was confirmed by pathologic evaluation of an excised skin nodule. The patient underwent laparoscopic right adrenalectomy through a transabdominal approach and was discharged on the second postoperative day, being normotensive. The patient is normotensive without antihypertensive therapy 11 years after the procedure. Conclusion Nowadays in the era of laparoscopy, patients with pheochromocytoma reach the operating theatre easier than in the past. Despite, the feasibility and oncological efficacy of the laparoscopic approach to the adrenals, continued long term follow-up is needed to establish the minimally invasive technique as the preferred approach. Furthermore, these patients should be further investigated for other neoplasias and stigmata of other neurocutaneous syndromes, taking into account the association of the familial pheochromo-cytoma with other familial basis inherited diseases.

  4. Identification of a protein that interacts with the nuclear factor-1 (NF-1) binding site in cells that do not express NF-1: comparison to NF-1, cellular distribution, and effect on transcription.

    OpenAIRE

    McQuillan, J J; Rosen, G.D.; Birkenmeier, T M; Dean, D C

    1991-01-01

    We examined expression of nuclear factor-1 (NF-1) in different cell lines. Expression was low or undetectable in T and B lymphocyte cell lines, whereas fibroblasts and other adherent cell lines generally had a relatively high level of NF-1 mRNA. In cell lines that did not express NF-1, gel retardation assays, nevertheless, indicated complexes between a protein or proteins and the NF-1 site. These complexes were less abundant than those formed with NF-1, they migrated more slowly, and they app...

  5. {sup 18}F-FDG PET/CT for detection of malignant peripheral nerve sheath tumours in neurofibromatosis type 1: tumour-to-liver ratio is superior to an SUV{sub max} cut-off

    Energy Technology Data Exchange (ETDEWEB)

    Salamon, Johannes [University Medical Centre Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); University Hospital Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Veldhoen, Simon [University Medical Centre Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); University Medical Centre Wuerzburg, Department of Diagnostic and Interventional Radiology, Wuerzburg (Germany); Apostolova, Ivayla [Otto-von-Guericke University, Department of Radiology and Nuclear Medicine, Magdeburg (Germany); Bannas, Peter; Yamamura, Jin; Herrmann, Jochen; Adam, Gerhard; Derlin, Thorsten [University Medical Centre Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Friedrich, Reinhard E. [University Medical Centre Hamburg-Eppendorf, Department of Oral and Maxillofacial Surgery, Hamburg (Germany); Mautner, Victor F. [University Medical Centre Hamburg-Eppendorf, Department of Neurology, Hamburg (Germany)

    2014-02-15

    To evaluate the usefulness of normalising intra-tumour tracer accumulation on {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to reference tissue uptake for characterisation of peripheral nerve sheath tumours (PNSTs) in neurofibromatosis type 1 (NF1) compared with the established maximum standardised uptake value (SUVmax) cut-off of >3.5. Forty-nine patients underwent FDG PET/CT. Intra-tumour tracer uptake (SUVmax) was normalised to three different reference tissues (tumour-to-liver, tumour-to-muscle and tumour-to-fat ratios). Receiver operating characteristic (ROC) analyses were used out to assess the diagnostic performance. Histopathology and follow-up served as the reference standard. Intra-tumour tracer uptake correlated significantly with liver uptake (r{sub s} = 0.58, P = 0.016). On ROC analysis, the optimum threshold for tumour-to-liver ratio was >2.6 (AUC = 0.9735). Both the SUVmax cut-off value of >3.5 and a tumour-to-liver ratio >2.6 provided a sensitivity of 100 %, but specificity was significantly higher for the latter (90.3 % vs 79.8 %; P = 0.013). In patients with NF1, quantitative {sup 18}F-FDG PET imaging may identify malignant change in neurofibromas with high accuracy. Specificity could be significantly increased by using the tumour-to-liver ratio. The authors recommend further evaluation of a tumour-to-liver ratio cut-off value of >2.6 for diagnostic intervention planning. (orig.)

  6. NF1 Mutations Are Common in Desmoplastic Melanoma.

    Science.gov (United States)

    Wiesner, Thomas; Kiuru, Maija; Scott, Sasinya N; Arcila, Maria; Halpern, Allan C; Hollmann, Travis; Berger, Michael F; Busam, Klaus J

    2015-10-01

    Desmoplastic melanoma (DM) is a rare variant of melanoma with distinct clinical, histopathologic, and immunohistochemical features. Clinically, DM differs from conventional melanoma by a higher propensity for local recurrence and less frequent metastatic spread to regional lymph nodes. In its pure form, DM has a distinct appearance displaying a low density of fusiform melanocytes in a collagen-rich matrix. Whereas a number of mutations have been identified in primary melanoma, including BRAF, NRAS, GNAQ, GNA11, and KIT, and the occurrence of these mutations has been found to correlate to some extent with the histopathologic features, anatomic site, and/or mode of sun exposure, no distinct set of mutations has so far been reported for DM. To study the potential association of neurofibromin (NF1) mutations with DM, we examined 15 desmoplastic and 20 non-DMs by next-generation sequencing. Mutations of the NF1 gene were found in 14 of 15 (93%) DMs and 4 of 20 (20%) non-DMs. The high frequency of NF1 mutations in DMs suggests an important role for NF1 in the biology of this type of melanoma.

  7. Drug Response and Resistance in Advanced NF1-Associated Cancers

    Science.gov (United States)

    2013-04-01

    Disease Retinal vein occlusion and neuropathies were uncommon but serious complications observed in patients enrolled in early phase trials of...that elevated levels of Ras-GTP plays a central role in tumorigenesis in NF1 suggests that inhibiting activated Ras is a logical therapeutic

  8. Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells.

    Science.gov (United States)

    Varin, Jennifer; Poulain, Laury; Hivelin, Mikael; Nusbaum, Patrick; Hubas, Arnaud; Laurendeau, Ingrid; Lantieri, Laurent; Wolkenstein, Pierre; Vidaud, Michel; Pasmant, Eric; Chapuis, Nicolas; Parfait, Béatrice

    2016-06-14

    Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive "active-site" mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.

  9. Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

    Science.gov (United States)

    Hivelin, Mikael; Nusbaum, Patrick; Hubas, Arnaud; Laurendeau, Ingrid; Lantieri, Laurent; Wolkenstein, Pierre; Vidaud, Michel; Pasmant, Eric; Chapuis, Nicolas; Parfait, Béatrice

    2016-01-01

    Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive “active-site” mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies. PMID:26840085

  10. Plexiform neurofibromatosis of vulva

    Directory of Open Access Journals (Sweden)

    Bharat B. Dogra

    2014-08-01

    Full Text Available Plexiform Neurofibromatosis of vulva is a rare, benign tumor of genital tract arising from nerve sheath of peripheral nerve. It may present as solitary lesion or as part of Von Recklinghausen's disease. Genitourinary neurofibroma is rare, however clitoris and labia majus happen to be the most frequent location of neurofibromatosis involving female genital tract. We present a case of plexiform neurofibroma arising from left labia majora in a young patient having features of Von Recklinghausens disease. She complained of discomfort while walking due to rubbing of pedunculated mass arising from her labia majora. We carried out the surgical excision of the mass followed by primary repair of labia majora. She has been followed up on out-patient basis for about three months without any recurrence so far. [Int J Res Med Sci 2014; 2(4.000: 1771-1773

  11. Cerebral glucose metabolism in neurofibromatosis type 1 assessed with [18F]-2-fluoro-2-deoxy-D-glucose and PET.

    OpenAIRE

    Balestri, P; Lucignani, G; Fois, A.; Magliani, L; Calistri, L; Grana, C.; Di Bartolo, R M; Perani, D; Fazio, F.

    1994-01-01

    Cerebral PET with [18F]-2-fluoro-2-deoxy-D-glucose has been performed in four patients with neurofibromatosis type 1 (NF1) to assess the relation between cerebral metabolic activity, MRI, and the presence of neurological symptoms, including seizures, as well as mental and language retardation. Widespread hypometabolism occurred in three of the patients. The lesions on MRI, which were localised in the subcortical white matter and grey structures, had normal rates of glucose metabolism. This fi...

  12. Spontaneous hemothorax caused by rupture of an intercostal artery aneurysm in neurofibromatosis Type I: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Chang Min; Na, Jae Beom; You, Jin Jong; Chung, Sung Hoon [Gyeongsang National Univ. College of Medicine, Pusan (Korea, Republic of)

    2001-01-01

    Neurofibromatosis type I (NF-1) is the most common neurocutaneous syndrome. Associated vascular abnormalities are arterial occlusion, aneurysm, ectasia and arteriovenous malformation. Spontaneous massive hemothorax due to rupture of an arterial aneurysm is rare but fatal. It is, therefore, essential to determine the location of an aneurysm and provide immediate surgical or the interventional treatment. We report a case of spotaneous hemothorax caused by rupture of an intercostal arterial aneurysm diagnosed by CT and angiography.

  13. Neurofibromatosis and pregnancy. An update.

    Science.gov (United States)

    Weissman, A; Jakobi, P; Zaidise, I; Drugan, A

    1993-11-01

    Neurofibromatosis is one of the most frequent genetic diseases in humans. Pregnancy in neurofibromatosis patients is, however, less common. Most current information on pregnancy and neurofibromatosis is derived from case reports, which may not reflect the true situation. In the past 15 years only two series of pregnant neurofibromatosis patients were reported in the English-language literature. We present our experience with 34 pregnancies in nine neurofibromatosis patients who delivered at our medical center. While fertility does not seem to be impaired in neurofibromatosis, these patients experience a higher-than-expected rate of first-trimester spontaneous abortions (20.7%), stillbirths (8.7%) and intrauterine growth retardation (13.0%). A high rate of cesarean section (26%) was also observed in our series. We conclude that pregnant neurofibromatosis patients constitute a high-risk group, in danger of developing life-threatening complications. However, with proper antenatal care, most pregnant neurofibromatosis patients can deliver safety if the pregnancy continues beyond the first trimester.

  14. Perforated appendiceal diverticulitis associated with appendiceal neurofibroma in neurofibromatosis type 1.

    Science.gov (United States)

    Ozaki, Akihiko; Tsukada, Manabu; Watanabe, Kazuo; Tsubokura, Masaharu; Kato, Shigeaki; Tanimoto, Tetsuya; Kami, Masahiro; Ohira, Hiromichi; Kanazawa, Yukio

    2015-09-07

    An appendiceal neurofibroma (ANF) is a rare neoplasm associated with neurofibromatosis type 1(NF-1), an inheritable neurocutaneous disorder that involves multiple systems including the intraabdominal organs. Appendiceal diverticulitis occasionally ruptures in the absence of intense abdominal pain, which can lead to serious consequences. Recent reports highlight the association between appendiceal diverticulum and appendiceal neoplasms; however, there is still little information on the association between appendiceal diverticulitis and ANF in NF-1. A 51-year-old Japanese male with NF-1 was referred to the division of surgery for mild right lower quadrant pain. It was suspected he had perforated acute appendicitis with periappendiceal abscess based on clinical manifestations and findings of computed tomography. An emergency appendectomy was conducted. The pathological examination revealed diffusely proliferated tumor cells of a neurofibroma, coexistent with multiple appendiceal diverticulums, leading to the diagnosis of perforated appendiceal diverticulitis associated with ANF. Although he developed a remnant abscess, he recovered with the conservative treatments of antibiotics and drainage. This case suggests that appendiceal diverticulitis might be a complication of appendiceal involvement of NF-1, and that it occasionally ruptures in the absence of intense abdominal pain. Clinicians should recognize that NF-1 can cause various abdominal manifestations.

  15. Mixed periampullary adenocarcinoma and somatostatinoma with small bowel gastrointestinal stromal tumour in neurofibromatosis type 1.

    Science.gov (United States)

    Tewari, Nilanjana; Rollins, Katie; Gandhi, Nirav; Kaye, Phillip; Lobo, Dileep N

    2014-11-28

    Gastrointestinal (GI) involvement is present in about one quarter of cases of neurofibromatosis type 1 (NF1). Adenocarcinomas have been reported in several organs. Gastrointestinal stromal tumors are the most common GI lesion seen in NFI. GISTs in combination with ampullary neuroendocrine tumors in NF-1 have been reported rarely. We present the case of a 44-year-old man who presented with a history of obstructive jaundice and weight loss. Investigations revealed a pancreatic tumor associated with a common bile duct (CBD) stricture. At operation, an ampullary adenocarcinoma that infiltrated into the head of pancreas with an adjacent somatostatinoma was found. In addition, a small bowel GIST was present. Mixed periampullary adenocarcinoma and somatostatinoma in a patient with NF1 has only been previously reported once. The current case highlights the spectrum of associated tumor types which can be seen in association with NF1. Patients with NF1 who present with jaundice and weight loss should be investigated in the usual manner with increased suspicion for duodenal and ampullary tumors.

  16. A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1

    Directory of Open Access Journals (Sweden)

    Nishi Takeshi

    2012-07-01

    Full Text Available Abstract Patients with neurofibromatosis-1 (NF-1 sometime develop neuroendocrine tumors (NET. Although these NETs usually occur in the duodenum or peri-ampullary region, they occasionally grow in the pancreas (PNET. A 62-year-old man with NF-1 had mild liver dysfunction and was admitted to our hospital for further examination. An abdominal contrast-enhanced computed tomography scan demonstrated a 30-mm tumor in the head of the pancreas. The scan showed an invasion of the tumor into the duodenum, and biopsy under an endoscopic ultrasonography indicated that the tumor was a NET. A subtotal stomach-preserving pancreaticoduodenectomy was performed. Macroscopically, the pancreatic tumor was white and elastic hard. Microscopically, tumor cells were composed of ribbons, cords, and solid nests with an acinus-like structure. The tumor was diagnosed as NET G2 according to the WHO classification (2010. The product of theNF-1 gene, i.e., neurofibromin, was weakly positive in the tumor cells, suggesting that the tumor was induced by a mutation in the NF-1 gene. This is the seventh case of PNET arising in NF-1 patients worldwide.

  17. Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior.

    Science.gov (United States)

    Krab, Lianne C; Oostenbrink, R; de Goede-Bolder, Arja; Aarsen, Femke K; Elgersma, Ype; Moll, Henriëtte A

    2009-03-01

    To investigate health-related quality of life (HR-QOL) in children with neurofibromatosis type 1 (NF1) with parental reports and children's self-reports, and to investigate the potential contribution of demographic factors, disease-specific factors, and problems in school performance or behavior. In a prospective observational study, parents of 58 children with NF1 (32 boys, 26 girls, age 12.2 +/- 2.5 years) visiting a university clinic, and their 43 children 10 years or older were assessed with the Child Health Questionnaire (CHQ). Potential determinants of domain scores were assessed in 3 explorative regression models. Parents reported a significant impact of NF1 on 9/13 CHQ scales, with moderate effect sizes on 8 (general health perceptions, physical functioning, general behavior, mental health, self esteem, family activities, role functioning emotional/behavioral, and parent emotional impact). Children report an impact on bodily pain, and an above average general behavior. Multiple CHQ scales were sensitive to demographic factors and behavioral problems, and 1 to NF1 severity. NF1 visibility and school problems did not influence HR-QOL. Parents, but not the children with NF1, report a profound impact of NF1 on physical, social, behavioral, and emotional aspects of HR-QOL. Multiple HR-QOL domains were most sensitive to behavioral problems, which points to an exciting potential opportunity to improve HR-QOL in children with NF1 by addressing these behavioral problems.

  18. Natural History of Plexiform Neurofibromas in NF1. Addendum

    Science.gov (United States)

    2008-10-01

    of the possibility of mea- suring tumor burden in neurofibromatosis 1. The semiautomatic segmentation technique in this study may allow quicker...abdomen, and pelvis), extremity, or head and neck. Each lesion was then graded with regard to nu- merous characteristics. Ten patients were reviewed...jointly by two radiologists to establish a grading system of these characteristics. The remaining 112 patients were reviewed by one radiologist. Subse

  19. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    Directory of Open Access Journals (Sweden)

    Stephanie White

    Full Text Available This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  20. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    Science.gov (United States)

    White, Stephanie; Marquez de Prado, Blanca; Russo, Andrew F; Hammond, Donna L

    2014-01-01

    This study examined whether mice with a deficiency of neurofibromin, a Ras GTPase activating protein, exhibit a nociceptive phenotype and probed a possible contribution by calcitonin gene-related peptide. In the absence of inflammation, Nf1+/- mice (B6.129S6 Nf1/J) and wild type littermates responded comparably to heat or mechanical stimuli, except for a subtle enhanced mechanical sensitivity in female Nf1+/- mice. Nociceptive phenotype was also examined after inflammation induced by capsaicin and formalin, which release endogenous calcitonin gene-related peptide. Intraplantar injection of capsaicin evoked comparable heat hyperalgesia and mechanical hypersensitivity in Nf1+/- and wild type mice of both genders. Formalin injection caused a similar duration of licking in male Nf1+/- and wild type mice. Female Nf1+/- mice licked less than wild type mice, but displayed other nociceptive behaviors. In contrast, intraplantar injection of CGRP caused greater heat hyperalgesia in Nf1+/- mice of both genders compared to wild type mice. Male Nf1+/- mice also exhibited greater mechanical hypersensitivity; however, female Nf1+/- mice exhibited less mechanical hypersensitivity than their wild type littermates. Transcripts for calcitonin gene-related peptide were similar in the dorsal root ganglia of both genotypes and genders. Transcripts for receptor activity-modifying protein-1, which is rate-limiting for the calcitonin gene-related peptide receptor, in the spinal cord were comparable for both genotypes and genders. The increased responsiveness to intraplantar calcitonin gene-related peptide suggests that the peripheral actions of calcitonin gene-related peptide are enhanced as a result of the neurofibromin deficit. The analgesic efficacy of calcitonin gene-related peptide receptor antagonists may therefore merit investigation in neurofibromatosis patients.

  1. Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

    Science.gov (United States)

    Silva, Gilberto; Ribeiro, Maria J; Costa, Gabriel N; Violante, Inês; Ramos, Fabiana; Saraiva, Jorge; Castelo-Branco, Miguel

    2016-01-01

    The limited capacity of the human brain to process the full extent of visual information reaching the visual cortex requires the recruitment of mechanisms of information selection through attention. Neurofibromatosis type-1 (NF1) is a neurodevelopmental disease often exhibiting attentional deficits and learning disabilities, and is considered to model similar impairments common in other neurodevelopmental disorders such as autism. In a previous study, we found that patients with NF1 are more prone to miss targets under overt attention conditions. This finding was interpreted as a result of increased occipito-parietal alpha oscillations. In the present study, we used electroencephalography (EEG) to study alpha power modulations and the performance of patients with NF1 in a covert attention task. Covert attention was required in order to perceive changes (target offset) of a peripherally presented stimulus. Interestingly, alpha oscillations were found to undergo greater desynchronization under this task in the NF1 group compared with control subjects. A similar pattern of desynchronization was found for beta frequencies while no changes in gamma oscillations could be identified. These results are consistent with the notion that different attentional states and task demands generate different patterns of abnormal modulation of alpha oscillatory processes in NF1. Under covert attention conditions and while target offset was reported with relatively high accuracy (over 90% correct responses), excessive desynchronization was found. These findings suggest an abnormal modulation of oscillatory activity and attentional processes in NF1. Given the known role of alpha in modulating attention, we suggest that alpha patterns can show both abnormal increases and decreases that are task and performance dependent, in a way that enhanced alpha desynchronization may reflect a compensatory mechanism to keep performance at normal levels. These results suggest that dysregulation of

  2. Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2.

    Science.gov (United States)

    Winter, Natalie; Rattay, Tim W; Axer, Hubertus; Schäffer, Eva; Décard, Bernhard F; Gugel, Isabel; Schuhmann, Martin; Grimm, Alexander

    2017-05-01

    The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  3. Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

    Directory of Open Access Journals (Sweden)

    Gilberto Silva

    Full Text Available The limited capacity of the human brain to process the full extent of visual information reaching the visual cortex requires the recruitment of mechanisms of information selection through attention. Neurofibromatosis type-1 (NF1 is a neurodevelopmental disease often exhibiting attentional deficits and learning disabilities, and is considered to model similar impairments common in other neurodevelopmental disorders such as autism. In a previous study, we found that patients with NF1 are more prone to miss targets under overt attention conditions. This finding was interpreted as a result of increased occipito-parietal alpha oscillations. In the present study, we used electroencephalography (EEG to study alpha power modulations and the performance of patients with NF1 in a covert attention task. Covert attention was required in order to perceive changes (target offset of a peripherally presented stimulus. Interestingly, alpha oscillations were found to undergo greater desynchronization under this task in the NF1 group compared with control subjects. A similar pattern of desynchronization was found for beta frequencies while no changes in gamma oscillations could be identified. These results are consistent with the notion that different attentional states and task demands generate different patterns of abnormal modulation of alpha oscillatory processes in NF1. Under covert attention conditions and while target offset was reported with relatively high accuracy (over 90% correct responses, excessive desynchronization was found. These findings suggest an abnormal modulation of oscillatory activity and attentional processes in NF1. Given the known role of alpha in modulating attention, we suggest that alpha patterns can show both abnormal increases and decreases that are task and performance dependent, in a way that enhanced alpha desynchronization may reflect a compensatory mechanism to keep performance at normal levels. These results suggest that

  4. Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Marc A. Wolman

    2014-09-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a common autosomal-dominant disorder associated with attention deficits and learning disabilities. The primary known function of neurofibromin, encoded by the NF1 gene, is to downregulate Ras activity. We show that nf1-deficient zebrafish exhibit learning and memory deficits and that acute pharmacological inhibition of downstream targets of Ras (MAPK and PI3K restores memory consolidation and recall but not learning. Conversely, acute pharmacological enhancement of cAMP signaling restores learning but not memory. Our data provide compelling evidence that neurofibromin regulates learning and memory by distinct molecular pathways in vertebrates and that deficits produced by genetic loss of function are reversible. These findings support the investigation of cAMP signaling enhancers as a companion therapy to Ras inhibition in the treatment of cognitive dysfunction in NF1.

  5. Angiogenesis and Therapeutic Approaches to NF1 Tumors

    Science.gov (United States)

    2007-04-01

    sheath tumor (MPNST), pheochromocytoma , astrocytoma, and juvenile myelomonocytic leukemia (Side and Shannon, 1998), that occur in the context of Nf1...implanted subcutaneously to provide physiological levels of the respective hormones. Xenografts of sNF96.2 cells were carried out as described above...xenografted sNF96.2 tumor cell proliferation when compared with xenografts in mice with intact ovaries (*Po0.0001). Replacement of physiological levels of

  6. Usefulness of Whole-Body Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography in Patients with Neurofibromatosis Type 1: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Giorgio Treglia

    2012-01-01

    Full Text Available Aim. To systematically review the role of positron emission tomography (PET with fluorine-18-fluorodeoxyglucose (FDG in patients with neurofibromatosis type 1 (NF1. Methods. A comprehensive literature search of published studies regarding FDG-PET and PET/CT in patients with NF1 was performed. No beginning date limit and language restriction were used; the search was updated until December 2011. Only those studies or subsets in studies including whole-body FDG-PET or PET/CT scans performed in patients with NF1 were included. Results. We identified 12 studies including 352 NF1 patients. Qualitative evaluation was performed in about half of the studies and semiquantitative analysis, mainly based on different values of SUV cutoff, in the others. Most of the studies evaluated the role of FDG-PET for differentiating benign from malignant peripheral nerve sheath tumors (MPNSTs. Malignant lesions were detected with a sensitivity ranging between 100% and 89%, but with lower specificity, ranging between 100% and 72%. Moreover, FDG-PET seems to be an important imaging modality for predicting the progression to MPNST and the outcome in patients with MPNST. Two studies evaluated the role of FDG-PET in pediatric patients with NF1. Conclusions. FDG-PET and PET/CT are useful methods to identify malignant change in neurogenic tumors in NF1 and to discriminate malignant from benign neurogenic lesions.

  7. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth.

    Science.gov (United States)

    Simmons, Grant W; Pong, Winnie W; Emnett, Ryan J; White, Crystal R; Gianino, Scott M; Rodriguez, Fausto J; Gutmann, David H

    2011-01-01

    Whereas carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression are heavily influenced by the local microenvironment. Previous studies from our laboratory have used Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we used CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times after ganciclovir administration. Ganciclovir-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma.

  8. Metachronous occurrence of nonradiation-induced brain cavernous hemangioma and medulloblastoma in a child with neurofibromatosis type I phenotype

    Directory of Open Access Journals (Sweden)

    Luciano L Furlanetti

    2012-01-01

    Full Text Available Cavernous hemangioma (CH is a sporadic vascular malformation occurring either as an autosomal dominant condition or as a well-known complication of radiation exposure. Medulloblastoma is a primitive neuroectodermal tumor common in children and currently treated with surgical resection, chemotherapy, and radiotherapy. Neurofibromatosis is the most common single-gene disorder of the central nervous system. Posterior fossa malignant tumors in the context of neurofibromatosis type I (NF1 are very infrequent. This is the first documented case of an unusual metachronous occurrence of non-radiation-induced CH and medulloblastoma in a child with NF1 phenotype. We report the case of a 13-month-old boy with cafι-au-lait skin lesions associated with NF1-like phenotype who underwent surgical resection of a single CH in the temporal lobe due to recurrent seizures. Four years later he presented with signs of raised intracranial pressure associated with a posterior fossa tumor and hydrocephalus, thus requiring gross total resection of the lesion. Histological analysis revealed a medulloblastoma. After being treated with radiotherapy and chemotherapy, he achieved total remission. Six years later a massive recurrence of the tumor was observed and the child eventually died. The interest in this case lies in the rarity of NF1-like phenotype associated with a non-radiation-induced brain CH and medulloblastoma in a child.

  9. Multifocal Head and Neck Neurofibromas with Osseous Abnormalities and Muscular Hypoplasia in a Child with Neurofibromatosis: Type I

    Directory of Open Access Journals (Sweden)

    Rachna Rath

    2016-01-01

    Full Text Available Neurofibromatosis type 1 (NF1 is a clinically and genetically distinct disease involving both neuroectodermal and mesenchymal derivatives. Orofacial manifestations in NF1 have been documented before but occurrence of multifocal intraosseous (IO and extraosseous (EO neurofibromas is rare. The present case highlights the importance of imaging findings in the diagnosis and management of multifocal jaw, infratemporal, and parotid neurofibromas with muscular hypoplasia in an eight-year-old girl with NF1. Apart from orthopantomograms (OPG, three-dimensional computed tomography (3D CT and cross-sectional reformations were valuable in delineating the extent of the lytic lesion and identifying additional bony deformities of the mandible. Magnetic resonance imaging (MRI helped to identify the solid nature of the lesion and true extent of the soft tissue mass.

  10. Spontaneous Involution of a Non-Optic Astrocytoma in Neurofibromatosis Type I: Serial Magnetic Resonance Imaging Evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Cakirer, S. [Istanbul Sisli Etfal Hospital (Turkey). Dept. of Radiology; Karaarslan, E. [VKV American Hospital, Istanbul (Turkey). Dept. of Radiology

    2004-10-01

    A patient with neurofibromatosis type I (NF1) was followed-up with serial magnetic resonance imaging (MRI) studies over a period of 6 years. A contrast-enhancing lesion of the internal capsule, histologically proven to be pilocytic astrocytoma through stereotactic brain biopsy with mass effect and associated edema, was detected to reveal spontaneous involution on follow-up MRI studies. Although spontaneous regression of gliomas of the optic pathway-hypothalamus in patients with NF1 is relatively common in the literature, spontaneous involution of non-optic (i.e. areas other than optic pathways and hypothalamus) gliomas is rarely reported. Conservative management with follow-up MRI studies should be considered for non-optic glial tumors and tumor-like masses in patients with NF1, and surgical treatment should not be considered unless the lesions exhibit a rapid or unrelenting growth on serial MRI studies or produce significant clinical deterioration.

  11. Multifocal Head and Neck Neurofibromas with Osseous Abnormalities and Muscular Hypoplasia in a Child with Neurofibromatosis: Type I.

    Science.gov (United States)

    Rath, Rachna; Kaur, Sheetal; Baig, Shadab Ali; Pati, Punyashlok; Sahoo, Sonalisa

    2016-01-01

    Neurofibromatosis type 1 (NF1) is a clinically and genetically distinct disease involving both neuroectodermal and mesenchymal derivatives. Orofacial manifestations in NF1 have been documented before but occurrence of multifocal intraosseous (IO) and extraosseous (EO) neurofibromas is rare. The present case highlights the importance of imaging findings in the diagnosis and management of multifocal jaw, infratemporal, and parotid neurofibromas with muscular hypoplasia in an eight-year-old girl with NF1. Apart from orthopantomograms (OPG), three-dimensional computed tomography (3D CT) and cross-sectional reformations were valuable in delineating the extent of the lytic lesion and identifying additional bony deformities of the mandible. Magnetic resonance imaging (MRI) helped to identify the solid nature of the lesion and true extent of the soft tissue mass.

  12. Charcot-Marie-Tooth syndrome and neurofibromatosis type 1 with multiple neurofibromas of the entire spinal nerve roots.

    Science.gov (United States)

    Onu, David O; Hunn, Andrew W; Peters-Willke, Jens

    2013-07-13

    The coexistence of polyneuropathy which has the definite clinical and electromyographical findings consistent with Charcot-Marie-Tooth (CMT) syndrome and neurofibromatosis type 1 (NF1) has infrequently been reported. We describe a patient with both CMT and NF1, who had multiple neurofibromas involving the entire spinal neural axis. In addition, he had multiple neurofibromas distributed within the ileopsoas and gluteus muscles and subcutaneous tissues. These lesions were detected readily by MRI and the patient underwent successful surgical resection of the largest tumours compressing bilateral C2 nerve roots. To our knowledge, this is the first reported case of CMT syndrome coexisting with NF1 in which multiple neurofibromas involved the entire spinal nerve roots. We discuss the diagnostic and therapeutic challenges, emphasising the role of MRI and electrophysiology in such cases and provide a literature review.

  13. [How to recognize neurofibromatosis?].

    Science.gov (United States)

    Peltonen, Sirkku; Pöyhönen, Minna; Koillinen, Hannele; Valanne, Leena; Peltonen, Juha

    2014-01-01

    Neurofibromatosis 1 is a hereditary symptom predisposing to cancer, affecting some 1,500 Finnish people. This systemic disease is most commonly detected through cutaneous findings. Although the cutaneous symptoms are harmless, they impair the patients' quality of life. The disease is, however, insidious, as the complications often become manifested from unexpected organ systems. For example cancers originally from nervous systems and severe bone lesions require rapid diagnosis and treatment. The healthcare personnel should thus be aware of the diagnosis of NF syndrome, and the patients should have sufficient knowledge of their disease.

  14. NF-1伴非萎缩型胸椎侧凸与胸弯型AIS及正常青少年矢状面形态的比较研究%Sagittal spino-pelvic alignment in non-dystrophic thoracic scoliosis secondary to NF-1 : a comparison with AIS and normal control

    Institute of Scientific and Technical Information of China (English)

    杨宗; 朱泽章; 邱勇; 王渭君; 周松; 沙士甫; 伍伟飞; 王守丰

    2013-01-01

    [目的]探讨青少年Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF-1)伴非萎缩型胸椎侧凸与青少年特发性脊柱侧凸(adolescent idiopathic scoliosis,AIS)患者及正常青少年矢状面脊柱、骨盆形态的差异.[方法]回顾分析2001年1月~2012年12月期间在本院手术治疗且侧凸Cobb角<70°的15例NF-1伴非萎缩型胸椎侧凸青少年患者(NF-1组).选择与NF-1患者年龄、性别、弯型以及侧凸Cobb角匹配的15例AIS患者(AIS组)进行比较,并以年龄、性别匹配的30名正常青少年作对照(control group,CTL组).全部研究对象均拍摄站立位全脊柱正侧位X线片并测量以下参数评估矢状面的形态:胸椎后凸角、胸腰段交界角、腰椎前凸角、骨盆入射角、骨盆倾斜角、骶骨倾斜角、脊柱倾斜度和脊柱骶骨角.采用单因素方差分析三组矢状面各参数的异同.[结果]15例NF-1患者中TK不足者及后凸畸形各1例,其余13例均为正常范围(10°~40°),NF-1组平均TK为(25.6±7.6)°,明显大于AIS组的(16.5±5.4)°(P <0.05);NF-1组LL为(-53.8±6.4)°,AIS为(-47.8±4.2)°,两者有显著性差异(P<0.05).NF-1组与CTL组比较显示各参数均无统计学差异(P>0.05).[结论]NF-1伴非萎缩型胸椎侧凸患者矢状面形态与正常青少年无明显差异:没有明显的胸椎后凸畸形,也无AIS患者明显胸椎后凸不足表现,提示此类患者术后远期矢状面上的并发症可能与术前的矢状面形态无明显相关性.%[Objective] To compare sagittal spino-pelvic alignment in neurofibromatosis type-1 (NF-1) associated with non-dystrophic thoracic scoliosis,adolescent idiopathic scoliosis (AIS),and normal control.[Methods] Fifteen NF-1 patients with non-dystrophic thoracic scoliosis (group NF-1) less than 70 degrees were reviewed.Fifteen AIS patients (group AIS) matched for age,gender,curve pattern and Cobb angle were selected for comparison.In addition,age-and gender-matched healthy

  15. Receptor Tyrosine Kinases as Targets for Treatment of Peripheral Nerve Sheath Tumors in NF 1 Patients

    Science.gov (United States)

    2010-03-01

    Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and kit-dependent bone marrow. Cell. 2008, 135(3):437-448...Nf1-dependent tumors require a microenvironment containing Nf1?/-and c-kit-depen- dent bone marrow. Cell 135(3):437–448 9. Gutmann DH, Aylsworth A... market . Since propolis, a very safe healthcare product from bee hives, contains anticancer ingredients called CAPE (caffeic acid phenethyl ester) or ARC

  16. Midkine Promoter-Driven Adenovirus as Potential Therapy for NF1

    Science.gov (United States)

    2006-12-01

    MPNST ). Abnormalities in the levels of growth factors are often associated with tumorigenesis, which is also the case with NF1 tumors. Midkine is...NF1 tumors and in the MPNST derived ST88-14 cells [1]. Presumably, the amount of transcription from the midkine promoter is higher in NF1 tumors and

  17. Neurofibromatosis Type 1 Associated with Hashimoto’s Thyroiditis: Coincidence or Possible Link

    Directory of Open Access Journals (Sweden)

    Junaid Nabi

    2013-01-01

    Full Text Available Introduction. Hashimoto's thyroiditis is a common form of chronic autoimmune thyroid disease (AITD and often coexists with other autoimmune diseases, but Hashimoto’s thyroiditis associated with an autosomal dominant neurofibromatosis type 1 is exceedingly rare. Case Presentation. A 30-year-old Bengali woman presented to the OPD with complaints of aching pain and tingling sensation in her hands and feet. Physical examination revealed dysmorphic facies, nodular swelling in the neck, cafe-au-lait spots, and neurofibromas covering the entire surface of her body. Her thyroid hormones were within normal limits. Thyroid ultrasound revealed a cystic area in the left lobe of the gland, and ultrasound-guided fine needle aspiration cytology revealed lymphocytic infiltration of the gland, suggesting Hashimoto’s thyroiditis. High levels of autoimmune antibodies such as antithyroglobulin and antimicrosomal antibodies confirmed the diagnosis. Conclusion. When encountered with a patient of Neurofibromatosis type 1, a physician should be careful about the possibility of a concomitant autoimmune disease. Clinical presentation of neurofibromatosis and Noonan syndrome often overlaps and recent studies have implicated a mutation in NF1 gene in the etiology of NFNS. More extensive reports and further investigations of such patients having combination of neurofibromatosis type 1 and autoimmune thyroiditis will certainly provide better understanding of this link in the near future.

  18. Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

    Science.gov (United States)

    Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

    2014-12-23

    Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

  19. Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition.

    Science.gov (United States)

    Petrella, L I; Cai, Y; Sereno, J V; Gonçalves, S I; Silva, A J; Castelo-Branco, M

    2016-09-01

    Neurofibromatosis type-1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain-behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1(+/-) ) using T2-weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1(+/-) mice have larger volumes than wild-type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate-putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure-function correlations were identified concerning social recognition performance and PFC volumes in Nf1(+/-) mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub-groups in Nf1(+/-) mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub-group of Nf1(+/-) mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  20. Morphologic and vasculature features of the choroid and associated choroid-retinal thickness alterations in neurofibromatosis type 1.

    Science.gov (United States)

    Abdolrahimzadeh, Solmaz; Felli, Lorenzo; Plateroti, Rocco; Plateroti, Andrea Maria; Giustini, Sandra; Calvieri, Stefano; Recupero, Santi Maria

    2015-06-01

    A normal structural and functional choroid is essential in supplying blood flow to the retina. Neurofibromatosis type 1 (NF1) is a neurocristopathy where the choroid is altered due to the presence of nodules. The present transversal study was conducted to examine choroidal nodules and their effect on choroidal and retinal thickness in NF1 patients. Near-infrared reflectance and optical coherence tomography with enhanced depth imaging were used to evaluate choroidal morphology and vasculature in 19 patients with NF1 and 19 healthy, age-matched control subjects. Choroidal thickness, neuroepithelium thickness, photoreceptors together with retinal pigment epithelium (RPE) thickness and outer nuclear layer (ONL) thickness were measured at the fovea and 1000 μm nasal, temporal, superior and inferior to the fovea in NF1 patients and control subjects. Choroidal and neuroepithelium thickness were assessed overlying and adjacent to nodules in NF1 patients. Choroidal nodules were classified as 'dome-shaped' or 'placcoid' subtypes in 17 patients. Small and medium calibre choroidal vessels were observed above dome-shaped nodules where choroidal thickness was significantly reduced. There was a statistically significant reduction in mean choroidal thickness (p=0.013) in NF1 patients with respect to control subjects. The neuroepithelium, photoreceptors together with RPE and ONL had a statistically significant reduction in mean thickness in NF1 patients (pchoroidal nodules which alter choroidal morphology and thickness. There is reduction in mean choroid thickness with generalised thinning of the neuroepithelium, photoreceptors together with RPE and ONL in NF1 patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  1. Age-related findings on MRI in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Gill, Deepak S. [Children' s Hospital at Westmead, The T. Y. Nelson Department of Neurology, Sydney, NSW (Australia); Hyman, Shelley L. [Children' s Hospital at Westmead, Neurogenetics Research Unit, Sydney (Australia); Steinberg, Adam [Children' s Hospital at Westmead, Department of Radiology, Sydney (Australia); North, Kathryn N. [Children' s Hospital at Westmead, The T. Y. Nelson Department of Neurology, Sydney, NSW (Australia); Children' s Hospital at Westmead, Neurogenetics Research Unit, Sydney (Australia)

    2006-10-15

    T2 hyperintensities (T2H) on MRI are the most common CNS lesions in individuals with neurofibromatosis type 1 (NF1). The aim was to determine the frequency, signal characteristics and localization of T2H at different ages. In addition, we examined the sensitivity of different MR imaging sequences in detecting these lesions. We studied prospectively a cohort of children, adolescents and young adults with NF1 using T2-volume (T2-V) and conventional MRI sequences. Lesions were designated as either discrete or diffuse, and the region of signal abnormality was recorded. A total of 103 patients were studied (age range 8.0-25.4 years, mean 13.9 years). The frequency, size, and intensity of T2H decreased with age in the basal ganglia (BG) and the cerebellum/brainstem (CB/BS). The majority of thalamic and CB/BS lesions were diffuse. Of the total cohort, 80% had diffuse bilateral hippocampal hyperintensities and 18.4% had hemispheric lesions best demonstrated on FLAIR; there was no significant difference in the frequency or signal intensity of hemispheric lesions with age. Lesions in the cerebral hemispheres and hippocampus imaged by MR do not change in prevalence over time, suggesting a different pathological basis from the lesions in the in BG and CB/BS that resolve with age. FLAIR and T2-V sequences are more sensitive in detecting lesions than standard T2-weighted sequences. (orig.)

  2. Neurofibromatosis: an update of ophthalmic characteristics and applications of optical coherence tomography

    Directory of Open Access Journals (Sweden)

    Abdolrahimzadeh B

    2016-05-01

    Full Text Available Barmak Abdolrahimzadeh,1 Domenica Carmen Piraino,2 Giorgio Albanese,2 Filippo Cruciani,2 Siavash Rahimi3 1Polimed Beltramelli Medical Center, Rome, Italy; 2Section of Ophthalmology, Department of Sense Organs, University of Rome “Sapienza”, Rome, Italy; 3Pathology Centre, Queen Alexandra Hospital, Portsmouth, UK Abstract: Neurofibromatosis (NF is a multisystem disorder and tumor predisposition syndrome caused by genetic mutation on chromosome 17-17q11.2 in NF type 1 (NF1, and on chromosome 22-22q12.2 in NF type 2. The disorder is characterized by considerable heterogeneity of clinical expression. NF1 is the form with the most characteristic ocular manifestations. Lisch nodules of the iris are among the well-known diagnostic criteria for the disease. Glaucoma and associated globe enlargement have been described in a significant proportion of patients with NF1 and orbital–facial involvement. Optic nerve glioma may cause strabismus and proptosis, and palpebral neurofibroma may reach considerable size and occasionally show malignant transformation. Near infrared reflectance has greatly contributed to enhancing our knowledge on choroidal alterations in NF1. Indeed, some authors have proposed to include these among the diagnostic criteria. Optical coherence tomography has given new insight on retinal alterations and is a noninvasive tool in the management of optic nerve gliomas in children. Ocular manifestations in NF type 2 can range from early-onset cataracts in up to 80% of cases to optic nerve hamartomas and combined pigment epithelial and retinal hamartomas. Keywords: neurofibromatosis, ophthalmic, optical coherence tomography, infrared reflectance, choroideal nodules, Lisch nodules

  3. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.

    Science.gov (United States)

    Plotkin, Scott R; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Esparza, Sonia; Merker, Vanessa L; Munn, Lance L; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F

    2012-01-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

  4. Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report

    Science.gov (United States)

    PONTI, GIOVANNI; PELLACANI, GIOVANNI; MARTORANA, DAVIDE; MANDEL, VICTOR DESMOND; LOSCHI, PIETRO; POLLIO, ANNAMARIA; PECCHI, ANNARITA; DEALIS, CRISTINA; SEIDENARI, STEFANIA; TOMASI, ALDO

    2016-01-01

    Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple cafè-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease. PMID:27284375

  5. Malignant Peripheral Nerve Sheath Tumors in Children with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Apostolos Pourtsidis

    2014-01-01

    Full Text Available Purpose. Malignant peripheral nerve sheath tumors (MPNSTs are rare in children and account for approximately 5–10% of all soft tissue sarcomas in adults. MPNSTs may occur independently but individuals with neurofibromatosis type 1 (NF1 have a significantly increased risk. Our aim is to present patients with MPNST treated in our department. Cases and Results. In this report we present 4 cases of MPNSTs (3 females: 13, 12, and 13 years old and 1 male: 10 years old arising in patients with NF1. All of them presented with an enlarging mass and pain at diagnosis. Tumor was located in the buttock, the spinal cord, the trunk, and the left leg proximal to the heel. Wide excision of the tumor and radiotherapy were applied to all and adjuvant chemotherapy was given to three of them after the disease was progressed. All four died 32, 18, 10, and 22 months after diagnosis with progressive disease locally and pulmonary metastases in two of them. Conclusions. In conclusion, MPNSTs arising in patients with NF1 are high grade sarcomas with short survival. Individuals with NF1 should be followed closely in order to identify early the development of MPNSTs. Aggressive surgery and complete excision significantly improves disease-free survival. The usefulness of radiation therapy in MPNSTs is not determined although all patients will receive radiation therapy at some stage of the disease. The role of chemotherapy is unclear.

  6. Autoimmune diseases associated with neurofibromatosis type 1.

    Science.gov (United States)

    Nanda, Arti

    2008-01-01

    Associations of autoimmune diseases with neurofibromatosis type 1 have been rarely described. In the present report, we describe two patients of neurofibromatosis type 1 having an association with vitiligo in one, and alopecia areata and autoimmune thyroiditis in another. The associations of neurofibromatosis type 1 with vitiligo, alopecia areata, and autoimmune thyroiditis have not been reported earlier. Whether these associations reflect a causal relationship with neurofibromatosis type 1 or are coincidental needs to be settled.

  7. Schwannomatosis: the overlooked neurofibromatosis?

    Science.gov (United States)

    Koontz, Nicholas A; Wiens, Andrea L; Agarwal, Atul; Hingtgen, Cynthia M; Emerson, Robert E; Mosier, Kristine M

    2013-06-01

    Schwannomas are typically benign tumors that occur sporadically, in neurofibromatosis type 2 (NF2), or in an entity called "schwannomatosis." Schwannomatosis patients develop multiple schwannomas without involvement of the vestibular apparatus. Geneticists, neurologists, and pathologists have recognized that schwannomatosis is distinct from NF2, but schwannomatosis remains unfamiliar to many radiologists. This article reviews the current medical literature, highlighting the similarities and differences between the schwannomatosis and NF2 phenotypes, genotypes, clinical manifestations, management considerations, and imaging findings. Imaging plays a critical role in diagnosing schwannomatosis, and a basic understanding of this syndrome is of interest to diagnostic radiologists. Moreover, it is imperative that radiologists be able to differentiate schwannomatosis from NF2 on imaging because there are significant differences in the management of these two diseases and clinical outcomes for affected patients.

  8. Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS.

    Directory of Open Access Journals (Sweden)

    David E Reuss

    Full Text Available Malignant peripheral nerve sheath tumor (MPNST is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1. We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.

  9. 神经纤维瘤病的影像学研究%Imaging findings of neurofibromatosis

    Institute of Scientific and Technical Information of China (English)

    武刚; 高晓龙; 黄丙仓; 王培军

    2011-01-01

    目的 探讨神经纤维瘤病(neurofibromatosis,NF)的分型和各型的影像学表现,提高对本病的认识.方法 收集16例经临床或手术证实的神经纤维瘤病例,对其影像学资料、临床表现进行回顾性的分析和总结.结果 根据美国国家卫生研究会提出的NF诊断标准,16例神经纤维瘤病中,NF-1型9例,NF-2型7例.与CT相比,MRI能够全面准确地显示病灶分布,病变大小、形态和信号特征以及与相邻组织结构的关系.结论 结合临床资料及影像表现,可以对神经纤维瘤病做出比较明确的诊断.MRI在检出神经纤维瘤病微小病灶等方面优于CT.%Objective To study the classification and imaging features of neurofibromatosis ( NF) .Methods The clinical data and imaging features of 16 patients with neurofibromatosis were retrospectively analyzed.Results According to the diagnostic standard established by the National Institute of Health ( NIH) conference, 9 cases were NF-1 and 7 cases were NF-2.MRI could well demonstrate the distribution, the size, the shape and the signal characteristics of neurofibromatosis.Conclusion Based on clinical materials and imaging features, neurofibromatosis can be definitelydiagnosed.MRI is superior to CT.

  10. Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only

    Directory of Open Access Journals (Sweden)

    D.G. Evans

    2016-05-01

    Interpretation: RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.

  11. Abnormal brain activation in neurofibromatosis type 1: a link between visual processing and the default mode network.

    Directory of Open Access Journals (Sweden)

    Inês R Violante

    Full Text Available Neurofibromatosis type 1 (NF1 is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low-level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M and parvocellular (P pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified.

  12. Multidimensional ultrasound and computed tomography imaging support in bleeding plexiform neurofibromatosis of the scalp: A case report and literature review

    Directory of Open Access Journals (Sweden)

    Ximena Wortsman

    2015-01-01

    Full Text Available Active bleeding in plexiform neurofibromatosis can be a life-threatening complication in neurofibromatosis type 1 (NF1. The prompt imaging support of 2D-3D ultrasound (US and computed tomography (CT during the active hemorrhage phase of cutaneous neurofibromas has not been previously reported. We report a case with NF1 who experienced a sudden swelling in the parieto-temporal region that corresponded to a massive and active hemorrhage within a plexiform neurofibroma. The US and CT imaging characteristics of this bleeding tumor are shown. Active hemorrhage in a plexiform neurofibroma of the scalp appeared in US as a heterogeneous hypodermal mass. CT demonstrated a fully hyperdense soft tissue mass. These characteristics differ from the non-complicated or old hemorrhagic imaging appearances of scalp plexiform neurofibromas and encourage prompt surgical treatment. This case report demonstrates the usefulness of imaging support in the early diagnosis of this hemorrhagic complication of NF1 in the scalp and also stimulates multispecialty management.

  13. GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice.

    Science.gov (United States)

    Park, Jong-In; Powers, James F; Tischler, Arthur S; Strock, Christopher J; Ball, Douglas W; Nelkin, Barry D

    2005-02-01

    Glial cell line-derived neurotrophic factor (GDNF) can induce neuron-like differentiation of mouse pheochromocytoma (MPC) cell lines derived from mice with a heterozygous knockout mutation of nf1, the murine counterpart of the human gene mutated in neurofibromatosis type 1 (NF1). Here, we show that GDNF-induced differentiation in the MPC 862L cell line is mediated by the MEK/extracellular signal-regulated kinase (ERK) pathway. Neurite outgrowth, increased expression of growth-associated protein 43, and decreased incorporation of bromodeoxyuridine (BrdU) were induced by treatment with GDNF, H-RasV12, or a constitutively active MEK2. GDNF also induces leukemia inhibitory factor (LIF) via the MEK/ERK pathway, and LIF itself can elicit these differentiative changes via a cell-extrinsic autocrine/paracrine pathway. Treatment with anti-LIF neutralizing antibody depleted the differentiative activity of the conditioned medium from cells stimulated for MEK/ERK signaling, while recombinant LIF could induce differentiation in MPC cells, indicating that LIF is the sole factor with differentiative activity. LIF could activate MEK1/2 and STAT3, but LIF-induced differentiation was blocked only by the MEK1/2-specific inhibitor U0126, indicating that the MEK/ERK pathway is necessary for LIF action in MPC cells. Our findings suggest that LIF may be utilized for signaling mediated by GDNF and may be important in the pathobiology of neuroendocrine tumors.

  14. Borderline lepromatous leprosy with neurofibromatosis

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    Angoori Gnaneshwar

    2010-01-01

    Full Text Available The coexistence of leprosy with neurofibromatosis is rare both the diseases present with nerve thickening and skin lesions (patches and nodules. The coexistence of neurofibroma with borderline tuberculoid, lepromatous, histoid, and neuritic leprosy has been reported in the past. We report here a case of borderline lepromatous leprosy coexisting with neurofibromatosis in a 60 year-old male, who presented with neurofibromata and nerve thickening. Histopathology of skin biopsy from the leprosy and neurofibroma nodules confirmed the diagnosis of leprosy and neurofibroma.

  15. Neurofibromatosis Type II

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    Akram Kasiri Ghahi

    2003-08-01

    Full Text Available Neurofibromatosis type 2 (NF2 is an inherited disease which is mainly characterized by the development of multiple schwannomas and meningiomas.  Incidence of the disease is about 1 in 60,000. Affected individuals inevitably develop schwannomas, typically affecting both auditory-vestibular nerve which lead in hearing loss and deafness. The majority of patients present with hearing loss, which is usually unilateral at onset and may be accompanied or preceded by tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease. NF II is caused by a defect in the gene that normally gives rise to a product called Merlin or Schwannomin, located on chromosome 22. Diagnosis is based on clinical and neuroimaging studies. Presymptomatic genetic testing is an integral part of the management of NF2 families. Prenatal diagnosis and pre-implantation genetic diagnosis is possible.

  16. Correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Makino S

    2014-01-01

    Full Text Available Shinji Makino, Hironobu Tampo, Yusuke Arai, Hiroto ObataDepartment of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, JapanAbstract: To evaluate correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1 (NF1, we examined ten cases with NF1 using near-infrared reflectance imaging. Patients ranged in age from 4 to 39 years. The angle used for near-infrared reflectance imaging was 55°. We counted the total number of choroidal abnormalities in an area within a 55° angle centered on the fovea and the total number of Lisch nodules on the iris by slit-lamp examination. No positive correlation was found between the number of Lisch nodules and patient age (Spearman's rank correlation coefficient ρ=0.117, P=0.7414. Choroidal abnormalities tended to increase with age (ρ=0.6150, but this difference was not statistically significant (P=0.0650. A positive correlation was found between the number of choroidal abnormalities and Lisch nodules (ρ=0.783, P=0.0267. In conclusion, choroidal abnormalities tend to increase with patient age and are correlated with the number of Lisch nodules.Keywords: neurofibromatosis type 1, near-infrared reflectance, choroidal abnormality, Lisch nodule, age

  17. Genetic and functional studies implicate synaptic overgrowth and ring gland cAMP/PKA signaling defects in the Drosophila melanogaster neurofibromatosis-1 growth deficiency.

    Directory of Open Access Journals (Sweden)

    James A Walker

    2013-11-01

    Full Text Available Neurofibromatosis type 1 (NF1, a genetic disease that affects 1 in 3,000, is caused by loss of a large evolutionary conserved protein that serves as a GTPase Activating Protein (GAP for Ras. Among Drosophila melanogaster Nf1 (dNf1 null mutant phenotypes, learning/memory deficits and reduced overall growth resemble human NF1 symptoms. These and other dNf1 defects are relatively insensitive to manipulations that reduce Ras signaling strength but are suppressed by increasing signaling through the 3'-5' cyclic adenosine monophosphate (cAMP dependent Protein Kinase A (PKA pathway, or phenocopied by inhibiting this pathway. However, whether dNf1 affects cAMP/PKA signaling directly or indirectly remains controversial. To shed light on this issue we screened 486 1(st and 2(nd chromosome deficiencies that uncover >80% of annotated genes for dominant modifiers of the dNf1 pupal size defect, identifying responsible genes in crosses with mutant alleles or by tissue-specific RNA interference (RNAi knockdown. Validating the screen, identified suppressors include the previously implicated dAlk tyrosine kinase, its activating ligand jelly belly (jeb, two other genes involved in Ras/ERK signal transduction and several involved in cAMP/PKA signaling. Novel modifiers that implicate synaptic defects in the dNf1 growth deficiency include the intersectin-related synaptic scaffold protein Dap160 and the cholecystokinin receptor-related CCKLR-17D1 drosulfakinin receptor. Providing mechanistic clues, we show that dAlk, jeb and CCKLR-17D1 are among mutants that also suppress a recently identified dNf1 neuromuscular junction (NMJ overgrowth phenotype and that manipulations that increase cAMP/PKA signaling in adipokinetic hormone (AKH-producing cells at the base of the neuroendocrine ring gland restore the dNf1 growth deficiency. Finally, supporting our previous contention that ALK might be a therapeutic target in NF1, we report that human ALK is expressed in cells that

  18. Renovascular hypertension in children with neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Peco-Antić Amira

    2003-01-01

    Full Text Available Arterial hypertension in pediatric patients with neurofibromatosis type 1 (NF 1 is usually due to renal artery stenosis (RAS mainly involving the proximal part of the vessel. The treatment modalities are highly individualized. In severe and/or bilateral RAS, antihypertensive drugs are either ineffective or have the potential risk for acute renal failure, while percutaneous transluminal angioplasty (PTA has limited success due to the ostial localization of RAS and the tough fibrotic tissue involved that is refractory to dilatation Renal autotransplantation has potential advantages when medical control and PTA/or bypass techniques failed. Here we report 5 year-old girl with NF 1 and hyponatremic hypertensive syndrome due to severe bilateral disease, occluded proximal part of the right artery and ostial stenosis (80% of the left one. Only left kidney was identified on 99 in Tc DTP A, but the right one was visualized on the renal ultrasonography and in the late phase of arterial renography due to well developed collateral circulation. Multiple antihyper-tensive drugs (nifedipine, labetolol and minoxidil in maximal doses and PTA failed to normalize BP while short term therapy with ACEIwith NF1 and hyponatremic hypertensive syndrome due to severe bilateral renovascular disease; occluded proximal part of the right renal artery and ostial stenosis (80% of the left one. Only left kidney was identified on 99m Tc DTPA, but the right one was visualized on the renal ultrasonography and in the late phase of arterial renography due to well developed collateral circulation. Multiple antyphypertensive drugs (nifedipine, labetolol and minoxidil in maximal doses and PTA failed to normalize BP while. short term therapy with ACEI, captopril induced transient acute renal failure. Autotransplantation of right kidney saved its function and improved BP control. Our current case Autotransplantation of right kidney saved its function and improved BP control. Our current

  19. Cognitive profile and disorders affecting higher brain functions in paediatric patients with neurofibromatosis type 1.

    Science.gov (United States)

    Vaucheret Paz, E; López Ballent, A; Puga, C; García Basalo, M J; Baliarda, F; Ekonen, C; Ilari, R; Agosta, G

    2017-04-18

    Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome often associated with specific cognitive deficits that are rarely monitored during follow-up of these patients. The purpose of our study is two-fold. First, we aimed to describe the cognitive profile of patients with NF1 and detect disorders in higher brain functions associated with the disease. Second, we identified the reasons for consultation associated with school performance in these patients. We conducted a descriptive cross-sectional study of 24 paediatric patients (ages 5 to 16) with NF1 who underwent neuropsychological assessment. The most frequent reasons for consultation were attention deficits (58.33%), learning disorders (25%), poor motor coordination (25%), and language impairment (0.8%). Although 96% of the patients displayed impairments in at least one of the assessed areas, only 83.34% of the parents had reported such impairments. Attention-deficit/hyperactivity disorder was present in 58.33% of the patients, whereas 33.33% had nonverbal learning disabilities, 20.83% had expressive language disorder, 8.33% had borderline intellectual functioning, 4.16% had mental retardation, and only 4.16% showed no cognitive impairment. Higher brain functions are frequently impaired in paediatric patients with NF1. Although many parents report such disorders, they can go undetected in some cases. Neuropsychological assessment is recommended for all paediatric patients with NF1 to detect cognitive impairment and provide early, effective rehabilitation treatment. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Lovastatin regulates brain spontaneous low-frequency brain activity in Neurofibromatosis type 1

    Science.gov (United States)

    Chabernaud, Camille; Mennes, Maarten; Kardel, Peter G.; Gaillard, William D.; Kalbfleisch, M. Layne; VanMeter, John W.; Packer, Roger J.; Milham, Michael P.; Castellanos, Francisco X.; Acosta, Maria T.

    2012-01-01

    In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as “continuous resting-state data” for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model. PMID:22433254

  1. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2007-10-01

    arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes & Development, 2002, 16:1060-1065. Kissil JL, Johnson KC, Eckman MS and...doubly mutant Nf1 and Wv hematopoietic cells. Blood 2003; 101: 1984-1986. Shannon, K.M. 35 Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe M, and... Paul E. McKeever, Shannon, K.M. 38 Megan Lim, Simon J. Conway, Luis F. Parada, Yuan Zhu, and Sean J. Morrison. 2007. The loss of Nf1 transiently

  2. Advance in the Pathogenesis of Neurofibromas in Neurofibromatosis Type 1%1型神经纤维瘤病肿瘤发生机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    程芙蓉; 李伟峰; 周列民

    2007-01-01

    1型神经纤维瘤病(neurofibromatosis 1,NF 1)是源于神经嵴细胞分化异常而导致的多系统损害的常染色体显性遗传病,至今其具体的发病机制仍不太清楚,现从NF1分子遗传学水平的改变、激素、端粒酶、促血管生成因子以及肿瘤微环境和电生理等方面对其进行了综述.

  3. The University of Utah Clinical Genetics Research Program as an NF1 Consortium Site

    Science.gov (United States)

    2007-02-01

    chair of the Biology Committee, and he organized a symposium of investigators and clinicians who were part of a MPNST (malignant peripheral nerve sheath...tumor) Consortium and the MPNST Committee of the NF1 Consortium that convened as a satellite meeting of the full NF1 Consortium meeting in Atlanta

  4. Regulation of the viability of Nf1 deficient cells by PKC isoforms.

    Science.gov (United States)

    Zhou, Xiaodong; Shen, Ling; Parris, Toshima; Huang, Junchi; Yi, Bo; Helou, Khalil; Chen, Changyan

    2014-11-15

    Suppression of protein kinase C (PKC) is known to be synthetically lethal with ras mutations in various types of cancer cells. The studies also showed that blockade of PKC affected the viability of Nf1 deficient cells. Since PKC family consists of more than 10 isoforms, our study aimed at identifying which isoform(s) played the crucial role in sensitizing Nf1 deficient cells to apoptosis. Using genetic and chemical PKC inhibitors, we demonstrated that the concurrent inhibition of PKC α and β induced Nf1 deficient ST or 96.2 cells, but not SNF02.2 cells with a normal Nf1 or ST cells ectopically expressing Nf1 effective domain gene, to apoptosis. In this process, PKC δ in Nf1 deficient cells, but not in ST/Nf1 cells, was upregulated and translocated to the nucleus. Furthermore, caspase 3 was cleaved and cytochrome c was released to the cytosol. Thus, it appeared that PKC δ and α/β are the crucial components for sustaining the aberrant Ras signaling and further viability of Nf1 deficient cells. The abrogation of these two isoforms activated their opponent PKC δ for switching on the caspase 3-governed apoptotic machinery.

  5. Neurofibromatosis with fully expressed Noonan syndrome.

    Science.gov (United States)

    Abuelo, D N; Meryash, D L

    1988-04-01

    We present an 18-year-old man with neurofibromatosis (NF) and classic manifestations of the Noonan syndrome (NS), including the cardiac findings. His father also has neurofibromatosis but only some of the characteristics of Noonan syndrome. This case lends further support to the notion that the neurofibromatosis-Noonan syndrome (NF-NS) is a discrete entity and demonstrates that the NF-NS can be inherited, with variable expression of the Noonan phenotype within a family.

  6. Recurrent hypoglycemia in a patient of neurofibromatosis type 1 and type 1 diabetes mellitus: Munchausen′s syndrome mimicking Insulinoma

    Directory of Open Access Journals (Sweden)

    Mubaraq Naqash

    2015-01-01

    Full Text Available A 35-year-old widow having neurofibromatosis type 1 (NF 1 and type 1 diabetes mellitus (DM was admitted for abdominal pain, vomiting and recent onset low blood sugars. During hospitalization, the patient developed recurrent episodes of hypoglycemia despite stopping insulin. A possibility of insulinoma was made due to the presence of abdominal pain, vomiting, hypoglycemia, and association of insulinoma with NF 1. However, surprisingly c-peptide was very low and plasma insulin levels were high. A detailed psychiatric evaluation of the patient revealed Munchausen′s syndrome as a cause of recurrent hypoglycemia. Unrecognized psychiatric illnesses in type 1 DM may lead to overzealous investigation. In conclusion, the clinical presentations of persons with factitious disorder are varied and impact every area of medicine, factitious causes should always be considered in unclarified recurrent hypoglycemia, especially in cases presented with dramatic but inconsistent medical history, and an unusual personal behavior.

  7. Neurofibromatosis tipo 1 en el embarazo: reporte de caso y revisión de la literatura

    OpenAIRE

    2016-01-01

    Introducción: La combinación de embarazo y Neurofibromatosis tipo 1 (NF1) ha sido reportada con frecuencias de 1/2.500 a 1/18.500 partos. Patología con manifestaciones que van desde lesiones cutáneas, tumores o complicaciones ortopédicas. En la mujer esta enfermedad podría empeorar durante la gestación, debido a la cantidad de receptores esteroidales que tendrían los neurofibromas y la posibilidad de malignización de tumores del sistema nervioso central. Presentación del Caso: Mujer de 22 año...

  8. Usefulness of {sup 18}F-FDG-PET/CT in Evaluating a Brainstem Glioma in an Adult Patient with Neurofibromatosis Type 1

    Energy Technology Data Exchange (ETDEWEB)

    Treglia, Giorgio [Oncology Institute of Southern Switzerland, Bellinzona (Switzerland); Muoio, Barbara; Del Ciello, Annemilia [Univ. of the Sacred, Rome (Italy); Bertagna, Francesco [Univ. of Brescia, Brescia (Italy)

    2013-09-15

    We describe a case of a brainstem glioma (BSG) occurred in an adult patient with neurofibromatosis type 1 (NF1) and evaluated by Flourine-18-Fluorodeoxyglucose-positron emission tomography/computed tomography ({sup 18}F-FDG-PET/CT). A 32-year-old male patient with NF1 underwent brain magnetic resonance imaging (MRI) for the onset of diplopia, facial paresis and cerebellar signs and symptoms. MRI showed a brainstem lesion compatible with BSG. Biopsy was not performed. {sup 18}F-FDG-PET/CT demonstrated intense {sup 18}F-FDG uptake in the brainstem lesion, suggesting an aggressive neoplasm. The patient was referred to radiotherapy but he developed rapid disease progression. In this case, {sup 18}F-FDG-PET/CT provided useful information about this rare NF1-associated tumor. Subsequently, the patient was referred to radiotherapy, but he developed rapid disease progression and died 3 months later. NF-1 is an autosomal dominant disorder characterized by multiple cafe-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. NF-1 is also characterized by low-grade tumors of the central and peripheral nervous system. There is also an increased risk of developing malignant tumors such as malignant peripheral nerve sheath tumors or central nervous system high-grade gliomas. NF1-associated BSGs are less common than NF1-associated optic gliomas (OGs) and seem to represent a particular entity which tend, as a whole, to have a more favorable prognosis and a more indolent course than BSGs in patients without NF1; nevertheless, some NF1-associted BSG may rapidly progress. {sup 18}F-FDG-PET/CT has demonstrated to provide useful information to the surveillance of OGs in children with NF1, particularly to identify progressive, symptomatic tumors. To the best of our knowledge, there are no data about the usefulness of {sup 18}F-FDG-PET/CT in adult patients with NF1-associated BSG. In our case, {sup 18}F-FDG-PET/CT has been useful in

  9. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Mautner, V.F.; Hartmann, M.; Kluwe, L.; Friedrich, R.E. [University Hospital Eppendorf, Section for Phakomatoses, Department of Maxillofacial Surgery, Hamburg (Germany); Fuensterer, C. [MRI Institute Hamburg-Othmarschen, Hamburg (Germany)

    2006-03-15

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3000. Approximately 30% of NF1 patients develop plexiform neurofibromas (PNF) which often cause severe clinical deficits. We studied the growth patterns of 256 plexiform neurofibromas (PNF) by magnetic resonance imaging (MRI) and associated disfigurement and functional deficits to determine whether there are definable growth types of these tumors. Retrospectively, we evaluated MRI scans obtained during 1997 to 2003 of 256 plexiform neurofibromas from 202 patients with NF1. Clinical investigation was carried out at the same time as the MRI scans. We identified three growth patterns: superficial in 59, displacing in 76, and invasive growth in 121 tumors. The majority (52%) of invasive PNF were found in the face, head and neck area. While superficial PNF primarily caused aesthetic problems, displacing PNF led in most cases to aesthetic problems and pain, while invasive PNF led mainly to functional deficits and disfigurement. Our study demonstrates that PNF have different growth patterns that are associated with specific clinical features. Classification of PNF may open new opportunities in clinical management, especially regarding decisions and options associated with surgical intervention. (orig.)

  10. Rib head protrusion into the central canal in type 1 neurofibromatosis

    Energy Technology Data Exchange (ETDEWEB)

    Ton, Jimmy; Yen, Philip [University of California, Davis Medical Center and U.C. Davis Children' s Hospital, Department of Radiology, Sacramento, CA (United States); Stein-Wexler, Rebecca [University of California, Davis Medical Center and U.C. Davis Children' s Hospital, Department of Radiology, Sacramento, CA (United States); Shriners Hospital of Northern California, Department of Radiology, Sacramento, CA (United States); Gupta, Munish [University of California, Davis Medical Center and U.C. Davis Children' s Hospital, Department of Orthopedic Surgery, Sacramento, CA (United States); Shriners Hospital of Northern California, Department of Orthopedic Surgery, Sacramento, CA (United States)

    2010-12-15

    Intraspinal rib head dislocation is an important but under-recognized consequence of dystrophic scoliosis in patients with neurofibromatosis 1 (NF1). To present clinical and imaging findings of intraspinal rib head dislocation in NF1. We retrospectively reviewed clinical presentation, imaging, operative reports and post-operative courses in four NF1 patients with intraspinal rib head dislocation and dystrophic scoliosis. We also reviewed 17 cases from the English literature. In each of our four cases of intraspinal rib head dislocation, a single rib head was dislocated on the convex apex of the curve, most often in the mid- to lower thoracic region. Cord compression occurred in half of these patients. Analysis of the literature yielded similar findings. Only three cases in the literature demonstrates the MRI appearance of this entity; most employ CT. All of our cases include both MRI and CT; we review the subtle findings on MRI. Although intraspinal rib head dislocation is readily apparent on CT, sometimes MRI is the only cross-sectional imaging performed. It is essential that radiologists become familiar with this entity, as subtle findings have significant implications for surgical management. (orig.)

  11. Somatostatinoma of the minor papilla treated by local excision in a patient with neurofibromatosis type 1.

    Science.gov (United States)

    Bhandari, Ramesh; Riddiough, Georgina; Lokan, Julie; Weinberg, Laurence; Efthymiou, Marios; Nikfarjam, Mehrdad

    2015-01-31

    Somatostatinoma arising from the minor papilla in a patient with neurofibromatosis type 1 (NF1) is a known but very rare condition, which may cause non-specific symptoms and can present because of its mass effect. A fifty-year-old female presenting with ongoing non-specific abdominal pain for a few months duration was found to have a mass involving the minor papilla. She had a history of NF1 but was otherwise well. Magnetic resonance imaging showed a dilated pancreatic duct and the finding of pancreatic divisum. The lesion was (18)fluorine-fluoro-2-deoxyglucose positron emission tomography/computed tomography and (68)gallium (Ga) DOTATATE negative. Endoscopic ultrasound revealed a 1.7 cm lesion confined to the minor ampulla. Endoscopic retrograde pancreatography attempts with biopsy and endoscopic ultrasound fine needle aspiration biopsy were inconclusive and resulted in mild pancreatitis on two occasions. Open local excision of the minor papilla was undertaken without complications. Histology confirmed a completely excised grade 1 neuroendocrine tumor with intense diffuse somatostatin staining. Somatostatinoma of the minor papilla is a rare tumor that most commonly occurs in the setting of NF1 and may be amenable to local excision.

  12. MRI findings in children with neurofibromatosis type 1: a prospective study

    Energy Technology Data Exchange (ETDEWEB)

    Van Es, S. [Dept. of Radiology, Royal Alexandra Hospital for Children, Paramatta (Australia); North, K.N. [Dept. of Neurology, Royal Alexandra Hospital for Children, Paramatta (Australia); McHugh, K. [Dept. of Radiology, Royal Alexandra Hospital for Children, Paramatta (Australia); De Silva, M. [Dept. of Radiology, Royal Alexandra Hospital for Children, Paramatta (Australia)

    1996-07-01

    To determine the frequency and nature of MRI lesions in children with neurofibromatosis type I (NF1), 50 patients aged 8 to 16 years were evaluated prospectively with cranial MRI. Forty-one children were asymptomatic with respect to central nervous system pathology, and 50% were macrocephalic. Sixteen patients (32%) had normal MRI examinations. Thirty-two patients (64%) had high intensity lesions of T2-weighted images and 16 patients (32%) had hyperintense lesions on T1-weighted images. Seven patients (14%) had ventricular dilatation (associated with increased intracranial pressure in 2) and 11 patients (22%) had optic pathway lesions (optic glioma in 7). MRI was superior to CT in differentiating optic sheath thickening and optic nerve tortuosity from optic glioma in four patients. An intracranial tumour (ependymoma) and sphenoid wing dysplasia were evident in individual patients. Findings previously unreported in NF1 included an aqueductal web resulting in hydrocephalus, intracular neurofibroma resulting in retinal detachment, and asymptomatic enlargement of the septum pellucidum. T1 and T2 signal abnormalities in isolation were not associated with neurological deficits or the occurrence of macrocephaly, and all lesions that required intervention were suspected clinically. Macrocephaly in the absence of increased intracranial pressure or accelerated head growth is not an indication for neuroimaging in children with NF1. However, the majority of children (68%) had disease-specific abnormalities and thus MRI may provide a useful adjunct to clinical evaluation in the diagnosis of equivocal cases. (orig.)

  13. Genetics Home Reference: neurofibromatosis type 2

    Science.gov (United States)

    ... Research Institute National Institute of Neurologic Disorders and Stroke Educational Resources (9 links) Centre for Genetics Education (Australia) Disease InfoSearch: Neurofibromatosis type 2 JAMA ...

  14. Partial unilateral lentiginosis is mosaic neurofibromatosis type 1 or not?

    Science.gov (United States)

    Yaşar, Şirin; Ersanli, Ayşegül; Göktay, Fatih; Aytekin, Sema; Cebeci, Dua; Güneş, Pembegül

    2017-01-01

    Partial unilateral lentiginosis (PUL) is a rare pigmentation disorder characterized by numerous lentigines with sharp margins in the midline in one or more dermatomes. Its segmental pattern suggests that this presentation accompanied by café-au-lait spots, Lisch nodule or neurofibromas has a close relationship with mosaic neurofibromatosis type 1 or segmental neurofibromatosis (NF) in particular. In a group of 16 patients with PUL, who presented at the dermatology outpatient clinic between 1998 and 2015, an examination was made of consanguineous marriage in the family history, the presence of a similar lesion or NF in first-degree relatives, neurofibroma in the physical examination, the involvement pattern, axillary/inguinal freckling and the presence and number of café-au-lait spots. The ophthalmological examination investigated Lisch nodule and optic glioma. The skeletal system was examined for NF involvement. Of 16 patients, 13 (81.2%) were female and three (18.8%) were male with a mean age of 31.19 years (range, 15-48). There was no family history of PUL in any case. Consanguineous marriage was absent in 15 patients (93.8%). While there were accompanying café-au-lait spots in three patients (18.8%). Lisch nodule was an accompanying finding in three patients (18.8%). Axillary freckling was detected in four (25%) patients. Neurofibroma was found in only one patient. Although café-au-lait spots, axillary freckling, neurofibroma and Lisch nodule were present in a small number of the patients, the presence of the findings may be considered to be specific to NF suggests that PUL is a variant of mosaic NF-1. Genetic studies will help to further elucidate this subject. © 2016 Japanese Dermatological Association.

  15. Whole body MR imaging in neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Meerbeeck, S.F.L. van [Department of Radiology and Medical Imaging, Ghent University, De Pintelaan 185, B-9000 Gent (Belgium)], E-mail: stephen.vm@rad-vanmeerbeeck.be; Verstraete, K.L. [Department of Radiology and Medical Imaging, Ghent University, De Pintelaan 185, B-9000 Gent (Belgium)], E-mail: koenraad.verstraete@ugent.be; Janssens, S.; Mortier, G. [Department of Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Gent (Belgium)

    2009-02-15

    Objective: To assess the value of whole body MR imaging in patients with neurofibromatosis type 1 (NF1). Materials and methods: 24 patients (15-59 years; mean and median 36 years; 7 males; 17 females) with genetically proven neurofibromatosis type 1 were examined with whole body MR imaging. Axial and coronal T1- and fat-suppressed T2-weighted images (slice thickness 6-12 mm) were acquired on a 1.5 T MR unit (Symphony; Siemens, Erlangen, Germany). The images were reviewed by 2 radiologists: 1 senior, 1 junior. The criterion for a neurofibroma was a mass lesion with low signal intensity on T1 and high signal intensity on T2, along the course of a nerve. The location, size, general morphology and course along plexuses and nerves were evaluated. Cutaneous and subcutaneous neurofibromas were defined as 'superficial' neurofibromas. The other neurofibromas were regarded as 'deep' neurofibromas. Results: There were no major problems to differentiate neurofibromas from lymph nodes, vessels or cysts. The latter three were easily recognised by their typical shape and location, whereas neurofibromas occurred in regions where no mass lesion was anatomically expected. There was no relation between age and total number of neurofibromas throughout the body. Classification according to location and number of neurofibromas: 8 patients had only superficial neurofibromas, 1 only deep and 15 both superficial and deep lesions. Twelve patients had less than 15 neurofibromas and 12 had more. Classification according to course: in 8 patients the neurofibromas occurred along plexuses or proximal part of the intercostal nerves; in 16 patients the lesions were more peripheral. Classification according to morphology: 4 patients had plexiform neurofibromas and 20 patients had multiple solitary lesions. Twelve of these 20 patients had less than 15 lesions, and 8 had more. In 2 patients multiple solitary neurofibromas occurred along the nerve in a chain configuration. In one

  16. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

    Science.gov (United States)

    Merker, Vanessa L; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Muzikansky, Alona; Nguyen, Rosa; Mautner, Victor F; Plotkin, Scott R

    2014-06-01

    Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis share a predisposition to develop multiple nerve sheath tumors. Previous studies have demonstrated that patients with NF1 and NF2 have reduced quality of life (QOL), but no studies have examined the relationship between whole-body tumor burden and QOL in these patients. We administered a QOL questionnaire (the SF-36) and a visual analog pain scale (VAS) to a previously described cohort of adult neurofibromatosis patients undergoing whole-body MRI. One-sample t-tests were used to compare norm-based SF-36 scores to weighted population means. Spearman correlation coefficients and multiple linear regression analyses controlling for demographic and disease-specific clinical variable were used to relate whole-body tumor volume to QOL scales. Two hundred forty-five patients (142 NF1, 53 NF2, 50 schwannomatosis) completed the study. Subjects showed deficits in selected subscales of the SF-36 compared to adjusted general population means. In bivariate analysis, increased tumor volume was significantly associated with pain in schwannomatosis patients, as measured by the SF-36 bodily pain subscale (rho = -0.287, P = 0.04) and VAS (rho = 0.34, P = 0.02). Regression models for NF2 patients showed a positive relationship between tumor burden and increased pain, as measured by the SF-36 (P = 0.008). Patients with NF1, NF2, and schwannomatosis suffer from reduced QOL, although only pain shows a clear relationship to patient's overall tumor burden. These findings suggest that internal tumor volume is not a primary contributor to QOL and emphasize the need for comprehensive treatment approaches that go beyond tumor-focused therapies such as surgery by including psychosocial interventions. © 2014 Wiley Periodicals, Inc.

  17. Clinical experience of surgically treating giant neurofibromatosis-1.

    Science.gov (United States)

    Chen, Baoguo; Xu, Minghuo; Song, Huifeng; Gao, Quanwen

    2017-02-01

    The surgical treatment for giant neurofibromatosis-1 (NF-1) requires comprehensive measures. Presently, there is no systematic description of surgical treatment. Because of its high level of risk, we want to share our clinical experience. From 2011 to 2014, patients (n = 8, 5 female and 3 male patients, aging from 31 to 45 years-old) were included in the study. The tumours were located on the trunk (n = 5) or face (n = 3). In addition to routine examination, blood storage was also prepared. Preoperative consultation from related departments was critical at first. Related artery embolisation was also carried out. In the operation, we checked thromboelastography, based on which reasonable blood component transfusion was implemented. Autologous blood transfusion was also ready. An instrument of copper needle or ring ligation was used to reduce haemorrhage before the surgery. Protruding or drooping portions of the tumours were excised. A pressurised bandage was applied when the surgery was completed. After the surgery, besides the routine monitoring of vital signs, re-haemorrhage should be detected in time. Then, we should decide whether blood transfusion or surgery was required again. Expanders were implanted in one female patient with facial injuries before removing the tumour. Then, expanded flaps were applied to repair the secondary wound. According to the above clinical route, after an average of 1-year follow-up, no patients died, and other unforeseen events did not occur. Wounds healed well in all patients. The tumor was excised as much as possible. No facial nerve paralysis occurred in the facial sites. Expanded flaps necrosis WAS not encountered. It is essential to design the educational clinical route for treating NF-1 when a giant protruding tumour is advised to be excised, which can minimise the risk of surgery and assure us of the maximum range of resection. © 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  18. Is executive function specifically impaired in children with neurofibromatosis type 1? A neuropsychological investigation of cognitive flexibility.

    Science.gov (United States)

    Roy, Arnaud; Barbarot, Sébastien; Roulin, Jean-Luc; Charbonnier, Valérie; Fasotti, Luciano; Stalder, Jean-François; Le Gall, Didier

    2014-01-01

    Our study investigated spontaneous versus reactive cognitive flexibility in children with neurofibromatosis type 1 (NF1) and their comorbidity with attention-deficit hyperactivity disorder (ADHD). Thirty children with NF1 aged 7 to 12 years old were compared to 60 healthy controls matched by age, gender, and parental education. On the basis of Eslinger and Grattan's definition ( 1993 ), spontaneous shifting was assessed using fluency tests, whereas reactive flexibility was measured by a child adaptation of the Modified Card-Sorting Test and the Brixton Test. IQ and basic skills were taken into account as confounding variables that might influence executive measures. NF1 children performed below the level of healthy children on both reactive flexibility tasks, even when intelligence and basic skills were partialled out, but ADHD symptomatology was not found to adversely affect the performance of patients. Our findings support the hypothesis of a specific executive impairment in NF1, uncovering a dissociation between (impaired) reactive flexibility and (preserved) spontaneous shifting, with no impact of ADHD on executive performance.

  19. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth

    Directory of Open Access Journals (Sweden)

    Anne C. Solga

    2015-10-01

    Full Text Available Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1 low-grade brain tumor (optic glioma, we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens, we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif ligand 5 (Ccl5 was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.

  20. In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells.

    Science.gov (United States)

    Allouche, Jennifer; Bellon, Nathalia; Saidani, Manoubia; Stanchina-Chatrousse, Laure; Masson, Yolande; Patwardhan, Anand; Gilles-Marsens, Floriane; Delevoye, Cédric; Domingues, Sophie; Nissan, Xavier; Martinat, Cécile; Lemaitre, Gilles; Peschanski, Marc; Baldeschi, Christine

    2015-07-21

    "Café-au-lait" macules (CALMs) and overall skin hyperpigmentation are early hallmarks of neurofibromatosis type 1 (NF1). One of the most frequent monogenic diseases, NF1 has subsequently been characterized with numerous benign Schwann cell-derived tumors. It is well established that neurofibromin, the NF1 gene product, is an antioncogene that down-regulates the RAS oncogene. In contrast, the molecular mechanisms associated with alteration of skin pigmentation have remained elusive. We have reassessed this issue by differentiating human embryonic stem cells into melanocytes. In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation. Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major players in melanogenesis. Finally, the hyperpigmentation phenotype can be rescued using specific inhibitors of these signaling pathways. These results open avenues for deciphering the pathological mechanisms involved in pigmentation diseases, and provide a robust assay for the development of new strategies for treating these diseases.

  1. Mortality Associated with Neurofibromatosis 1: A Cohort Study of 1895 Patients in 1980-2006 in France

    Science.gov (United States)

    2011-01-01

    Background Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006. Methods Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death. Results Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%). Conclusions We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males. PMID:21542925

  2. Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells.

    Science.gov (United States)

    Zhou, Xiaodong; Kim, Sung-Hoon; Shen, Ling; Lee, Hyo-Jung; Chen, Changyan

    2014-01-01

    Mutations of tumor suppressor Nf1 gene deregulate Ras-mediated signaling, which confers the predisposition for developing benign or malignant tumors. Inhibition of protein kinase C (PKC) was shown to be in synergy with aberrant Ras for the induction of apoptosis in various types of cancer cells. However, it has not been investigated whether loss of PKC is lethal for Nf1-deficient cells. In this study, using HMG (3-hydroxy-3-methylgutaryl, a PKC inhibitor), we demonstrate that the inhibition of PKC by HMG treatment triggered a persistently mitotic arrest, resulting in the occurrence of mitotic catastrophe in Nf1-deficient ST8814 cells. However, the introduction of the Nf1 effective domain gene into ST8814 cells abolished this mitotic crisis. In addition, HMG injection significantly attenuated the growth of the xenografted ST8814 tumors. Moreover, Chk1 was phosphorylated, accompanied with the persistent increase of cyclin B1 expression in HMG-treated ST8814 cells. The knockdown of Chk1 by the siRNA prevented the Nf1-deficient cells from undergoing HMG-mediated mitotic arrest as well as mitotic catastrophe. Thus, our data suggested that the suppression of PKC activates the Chk1-mediated mitotic exit checkpoint in Nf1-deficient cells, leading to the induction of apoptosis via mitotic catastrophe. Collectively, the study indicates that targeting PKC may be a potential option for developing new strategies to treat Nf1-deficiency-related diseases.

  3. Zebrafish as a Model to Study NF1-Associated Learning Deficits

    Science.gov (United States)

    2015-05-01

    longer- term, protein-synthesis-dependent habituation). Importantly, habituation reflects a highly conserved form of attention-based learning and...neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons. Genes Dev. 20, 3311– 3323. Walker...and functional studies implicate synaptic overgrowth and ring gland cAMP/PKA signaling defects in the Drosophila melanogaster neurofibromatosis-1

  4. Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area.

    Science.gov (United States)

    Wang, X; Levin, A M; Smolinski, S E; Vigneau, F D; Levin, N K; Tainsky, M A

    2012-12-01

    Neurofibromatosis type 1 (NF1) is one of the most common cancer predisposing syndromes with an incidence of 1 in 3,500 worldwide. Certain neoplasms or malignancies are over-represented in individuals with NF1; however, an increased risk of breast cancer has not been widely recognized or accepted. We identified 76 women with NF1 seen in the Henry Ford Health System (HFHS) from 1990 to 2009, and linked them to the Surveillance Epidemiology and End Results (SEER) registry covering the metropolitan Detroit area. Fifty-one women (67%) were under age 50 years at the time of data analysis. Six women developed invasive breast cancer before age 50, and three developed invasive breast cancer after age 50. Using standardized incidence ratios (SIRs) calculated based on the SEER age-adjusted invasive breast cancer incidence rates, our findings demonstrated a statistically significant increase of breast cancer incidence occurring in NF1 women (SIR = 5.2; 95% CI 2.4-9.8), and this relative increase was especially evident among those with breast cancer onset under age 50 (SIR = 8.8; 95% CI 3.2-19.2). These data are consistent with other reports suggesting an increase in breast cancer risk among females with NF1, which indicate that breast cancer screening guidelines should be evaluated for this potentially high-risk group.

  5. Utility of positron emission tomography for tumour surveillance in children with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Moharir, Mahendranath [Hospital for Sick Children, Division of Neurology, Ontario (Canada); London, Kevin [Children' s Hospital at Westmead, Department of Nuclear Medicine, Sydney (Australia); Howman-Giles, Robert [University of Sydney, Discipline of Imaging, Faculty of Medicine, Sydney (Australia); North, Kathryn [Children' s Hospital at Westmead, Institute for Neuroscience and Muscle Research, Sydney, NSW (Australia)

    2010-07-15

    There is little consensus regarding optimal surveillance of optic pathway glioma (OPG) and plexiform neurofibroma (PNF) in childhood neurofibromatosis type 1 (NF1). {sup 18}F-2-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography and computed tomography (PET/CT) is employed in the surveillance of adult PNFs; but its utility has neither been specifically studied in children with PNFs nor in children with OPG. Review of PET/CT studies was performed in NF1 children with OPG or PNF. FDG-avidity of tumours was semi-quantitatively analysed and graded by calculating the maximum standardised uptake value (SUV{sub max}) [grade 1: <3 (low), grade 2: >3-<4 (intermediate), grade 3: >4 (intense)]. Eighteen children (ten girls; median age: 8.5-years) had PET/CT. Nineteen OPGs were imaged. The SUV{sub max} could be measured in 16. Ten were grade 1 and three each were grade 2 and grade 3. FDG-avidity reduced from grade 3 to grade 1 in two symptomatic OPGs following chemotherapy and this was associated with clinical improvement. PET/CT diagnosed symptomatic OPGs with a sensitivity of 0.625 [95% confidence interval (CI): 0.259-0.897] and specificity of 0.875 (95% CI: 0.466-0.993). Sixteen PNFs were imaged. Twelve were grade 1 and two each were grade 2 and grade 3. The two grade 3 PNFs were confirmed malignant peripheral nerve sheath tumours. PET/CT diagnosed malignant transformation with a sensitivity of 1.0 (95% CI: 0.197-1.0) and specificity of 0.857 (95% CI: 0.561-0.974). PET/CT may contribute useful information to the surveillance of OPG in childhood NF1 - particularly to identify progressive, symptomatic tumours. As in adults, PET/CT is useful for the detection of malignant transformation in PNFs in children with NF1. (orig.)

  6. Bone mineral density in children and young adults with neurofibromatosis type 1.

    Science.gov (United States)

    Lodish, Maya B; Dagalakis, Urania; Sinaii, Ninet; Bornstein, Ethan; Kim, Aerang; Lokie, Kelsey B; Baldwin, Andrea M; Reynolds, James C; Dombi, Eva; Stratakis, Constantine A; Widemann, Brigitte C

    2012-12-01

    Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2-24.8; mean 13.7 ± 4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2-4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score ≤-2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (-1.60 ± 1.26) were more impaired compared with both the FN (-0.54 ± 1.58; P=0.0003) and the whole-body BMC/height Z-scores (-1.16 ± 0.90; P=0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (r(s)=-0.36, P=0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height.

  7. Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature.

    Science.gov (United States)

    Vranceanu, Ana-Maria; Merker, Vanessa L; Park, Elyse R; Plotkin, Scott R

    2015-04-01

    The aim of this research is to identify, within a systematic review, aspects of quality of life (QoL) that are adversely affected in children and adolescents with neurofibromatosis (NF), and to report predictors of quality of life in this population. Published reports of original research were included if they described QoL in children and/or adolescents with NF, and met methodological quality according to a list of predefined criteria. Seven studies conducted between 2006 and 2013 met inclusion criteria. All seven studies examined patients with NF1 and reported that these patients have lower general QoL compared to population norms. Parents' proxy ratings of QoL were generally lower than children's self-report ratings. By parent proxy, familial NF1 was a strong protective factor for QoL, while the opposite was found by child report. By parent proxy, male sex was significantly associated with lower scores on the parental time impact of QoL. Skin-related QoL was only slightly altered in this population, vision-specific QoL was impacted only in patients with vision loss. The majority of findings regarding predictors of QoL in children with NF1 were weak, due to a lack of studies, heterogeneity of samples, and heterogeneity of measurements/predictors assessed. Future studies should examine more comprehensively the psychosocial factors affecting the NF population, especially in young patients with NF2 and schwannomatosis, who have been neglected in prior research. The use of consistent QoL measures is preferred to allow better comparison among studies and conditions. Interventions, including comprehensive mind-body treatments, are warranted to address impaired QoL in children and adolescents with NF1.

  8. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2009-10-01

    can result in cosmetic , orthopedic, and neurologic disabilities. Optic nerve gliomas are another vexing clinical problem. Although histologically...implications for treating the complications of NF1 disease as many pharmaceutical and biotechnology companies are actively developing and evaluating...immunopanning (B). Astrocytes are marked with GFAP (red) and Pax-2 (green). DAPI staining of cellular nuclei in blue . Shannon, K.M. 13 3). This

  9. Neurofibromatosis and lessons for the war on cancer.

    Science.gov (United States)

    Reilly, Karlyne M

    2009-07-01

    In the war on cancer, a great deal of attention is being paid to knowing the 'enemy'. It is widely believed that by understanding the driving forces underlying cancer, researchers can develop better ways to target the disease. Currently, large-scale efforts have been under taken to completely characterize molecular changes in common human cancers (http://cancergenome.nih.gov/) (Collins & Barker, 2007). However, as more is learned about cancer, the debate increases on what exactly the enemy is: cells making up the bulk of the tumour, rare tumour stem cells that can regrow the tumour, tumour microenvironment, the subset of cancer cells with metastatic potential, etc. Studies of the cancers associated with Neurofibromatosis type 1 (NF1) are helping to define the relationship between many of these different cell types. It is still unclear how these different enemies are related to each other and how they interact to wage cancer's war on the patient. 'If you know the enemy and know yourself you need not fear the results of a hundred battles.' - Sun Tzu, The Art of War, c. 500 B.C.

  10. Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

    Science.gov (United States)

    2016-08-01

    behavioral and cognitive testing than originally anticipated. In addition, as a minimal number of mice was provided to us for breeding of the NF1 and Alk...AWARD NUMBER: W81XWH-13-1-0117 TITLE: Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice...including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and

  11. miR-107 regulates tumor progression by targeting NF1 in gastric cancer.

    Science.gov (United States)

    Wang, Shizhi; Ma, Gaoxiang; Zhu, Haixia; Lv, Chunye; Chu, Haiyan; Tong, Na; Wu, Dongmei; Qiang, Fulin; Gong, Weida; Zhao, Qinghong; Tao, Guoquan; Zhou, Jianwei; Zhang, Zhengdong; Wang, Meilin

    2016-11-09

    Our previous genome-wide miRNA microarray study revealed that miR-107 was upregulated in gastric cancer (GC). In this study we aimed to explore its biological role in the pathogenesis of GC. Integrating in silico prediction algorithms with western blotting assays revealed that miR-107 inhibition enhanced NF1 (neurofibromin 1) mRNA and protein levels, suggesting that NF1 is one of miR-107 targets in GC. Luciferase reporter assay revealed that miR-107 suppressed NF1 expression by binding to the first potential binding site within the 3'-UTR of NF1 mRNA. mRNA stable assay indicated this binding could result in NF1 mRNA instability, which might contribute to its abnormal protein expression. Functional analyses such as cell growth, transwell migration and invasion assays were used to investigate the role of interaction between miR-107 and its target on GC development and progression. Moreover, We investigated the association between the clinical phenotype and the status of miR-107 expression in 55 GC tissues, and found the high expression contributed to the tumor size and depth of invasion. The results exhibited that down regulation of miR-107 opposed cell growth, migration, and invasion, whereas NF1 repression promoted these phenotypes. Our findings provide a mechanism by which miR-107 regulates NF1 in GC, as well as highlight the importance of interaction between miR-107 and NF1 in GC development and progression.

  12. Giant malignant peripheral nerve sheath tumor of thigh in an adolescent with neurofibromatosis type 1: a case report

    Directory of Open Access Journals (Sweden)

    Tosun HB

    2015-10-01

    Full Text Available Haci Bayram Tosun,1 Sancar Serbest,2 Bilge Aydin Turk,3 Seyit Ali Gumustas,1 Abuzer Uludag1 1Department of Orthopaedics and Traumatology, Faculty of Medicine, Adiyaman University, Adiyaman, 2Department of Orthopaedics and Traumatology, Faculty of Medicine, Kirikkale University, Kirikkale, 3Department of Pathology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey Abstract: Malignant peripheral nerve sheath tumors (MPNSTs are rare sarcomas of children and adolescents, and they are aggressive tumors with a high rate of local recurrence. We present a 15-year-old boy with neurofibromatosis type 1 (NF1, who had a giant MPNST on the right thigh taking into account the available literature. Diagnosis of MPNST may be delayed in NF1 patients due to confusion with a neurofibroma and/or a plexiform neurofibroma. Malignancy should be considered, especially in cases with big masses, with heterogeneous involvement, or in the presence of cysts or necrotic nodules. The aim of surgical treatment is complete surgical excision. Keywords: nerve sheath neoplasm, sarcoma, adolescent, neurofibromatosis, lower extremity

  13. RESEARCH PROGRESS OF PATHOGENESIS MECHANISM OF SPINAL DEFORMITY IN NEUROFIBROMATOSIS TYPE 1%1型神经纤维瘤病相关脊柱畸形致病机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    杨辉亮; 周春光; 宋跃明

    2016-01-01

    目的 综述1型神经纤维瘤病(neurofibromatosis type 1,NF1)相关的脊柱畸形致病机制研究进展.方法 广泛查阅近年国内外有关NF1相关脊柱畸形致病机制的文献,对其与脊柱畸形的相互联系、相关致病机制及研究进展进行综述.结果 目前对于NF1患者发生脊柱畸形的致病机制尚未明确,可能与神经纤维瘤直接侵蚀与压迫、椎管内硬脊膜扩张、褪黑素导致的脊柱旁肌肉收缩力下降、骨量减少与骨质疏松、性早熟以及中胚层发育不良有关.结论 NF1患者的众多临床表现可能是导致其脊柱畸形发生的诱因,NF1相关脊柱畸形致病机制的研究将有助于对NF1脊柱畸形的认识、诊断和治疗.

  14. Treatment of ADHD in Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-04-01

    Full Text Available The cognitive and behavioral problems and effects of treatment of attention deficit hyperactivity disorder (ADHD in 20 children with NF1 and ADHD were compared to 26 control children with NF1, 14 controls with ADHD, and 14 controls with normal development, studied at Klinikum Nord Ochsenzoll. Hamburg, Germany.

  15. The association between glomus tumors and neurofibromatosis.

    Science.gov (United States)

    Harrison, Bridget; Moore, Amy M; Calfee, Ryan; Sammer, Douglas M

    2013-08-01

    To determine whether an epidemiologic association exists between glomus tumors and neurofibromatosis. Using a pathology database, we established a study cohort consisting of all patients who had undergone excision of a glomus tumor of the hand between 1995 and 2010. We created a control cohort by randomly selecting 200 patients who had undergone excision of a ganglion cyst over the same period. We reviewed medical records for each cohort to identify patients with a diagnosis of neurofibromatosis. We calculated the odds ratio was calculated and performed Fisher's exact test to determine the significance of the association. We identified 21 patients with glomus tumors of the hand. Six of these patients carried the diagnosis of neurofibromatosis (29%). In contrast, no patients in the control group carried the diagnosis of neurofibromatosis. The odds ratio for a diagnosis of neurofibromatosis in association with a glomus tumor compared with controls was 168:1. This study provides evidence of a strong epidemiologic association between glomus tumors and neurofibromatosis. Glomus tumor should be included in the differential diagnosis in neurofibromatosis patients who present with a painful lesion of the hand or finger. Diagnostic III. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

  16. Neurofibromatosis revisited: A pictorial review

    Directory of Open Access Journals (Sweden)

    Nausheen Khan

    2010-03-01

    Full Text Available Neurofibromatosis (or von Recklinghausen disease is a hereditary condition due to mesodermal and neuroectodermal dysplasia, eponymously named after the researcher who reported it in 1882. The disorder is transmitted as an autosomal dominant condition, but 50% of cases arise as spontaneous mutations. The incidence falls within the range 1:2 000 - 1:4 000, and has no gender bias. We present a series of images produced by different modalities that show lesions and pathologies that are characteristic of the disease.

  17. Neurofibromatosis type 1 and Chiari type 1 malformation: A case report and literature review of a rare association

    Science.gov (United States)

    Pozetti, Marianne; Belsuzarri, Telmo Augusto Barba; Belsuzarri, Natalia C. B.; Seixas, Naira B.; Araujo, João F. M.

    2016-01-01

    Background: The association between neurofibromatosis type 1 (NF-I) and Chiari I malformation (CMI) is rare, and not many studies are reported in the literature. Performing magnetic resonance imaging (MRI) in patients with NF-1 is essential because several cases of Chiari type I are completely asymptomatic. We emphasize the need for inclusion of Chiari I as diagnosis in association with NF-1. Case Description: The patient was a 51-year-old black man who presented with complaints of pain and decreased motion and sensibility of his hands, wrists, and forearms, along with progressive dysarthria. Even though the computed tomography (CT) scan of the skull did not show changes, the MRI showed hydro/syringomyelia in the cervical spine area. Midline suboccipital craniectomy with total laminectomy of c1 and partial laminectomy of c2 was performed; tonsillectomy was also performed for cistern expansion because of intense thickening and obliteration of the obex by the cerebellar tonsils. Following treatment, the patient showed remission of symptoms. Conclusion: NF-1 in association with CMI is rare, and early diagnosis and surgical treatment are essential to slow down the myelopathy; although they prevent neurological damages, patients with NF-1 must remain under doctor's attention in case of association with CMI. Our literature review showed that symptoms can vary and include headache, gait disturbance, and sensory/motor diminution, until asymptomatic patients. Moreover, the incidence of NF-1 is considerably higher in CMI patients in comparison to the global incidence (8.6–11.8% and 0.775%, respectively). The surgical technique must be evaluated case by case according to the degree of cerebrospinal fluid obstruction. PMID:27500008

  18. Preclinical Mouse Models of Neurofibromatosis

    Science.gov (United States)

    2005-11-01

    245. Kushner, B.H., Heller, G., Cheung, N.K., Wollner, N., Kramer, K., Bajorin, D., Polyak , T., and Meyers, P.A. (1998). High risk of leukemia after...with the SVZ. LV , lat- eral ventricle.contained tumor cells spreading on the surface of the brain (Figure 8A). We also obtained two GBM tumor samples...associated optic gliomaDevelopment and disease zone of the lateral ventricle ( LV ; Fig. 5C) (Gage, 2000). In brains of a subset of aged Nf1hGFAPKO

  19. Analysis of two cases with bronchopulmonary neurofibromatosis

    Directory of Open Access Journals (Sweden)

    Yuan Ting

    2012-07-01

    Full Text Available Abstract Neurogenic tumor of lung is very rare. Only few cases have been reported in the literature. We present here two cases of bronchopulmonary neurofibromatosis in two adults. In both cases, attempts at imaging failed to diagnose the case, and it was the histological study that ensured the diagnosis of neurofibromatosis. Biopsy specimens showed bundles of spindle-shaped cells mixed with collagen, and on immunohistochemistry some cells were positive for S-100 protein.

  20. Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients.

    Science.gov (United States)

    Harder, Anja; Wesemann, Martin; Hagel, Christian; Schittenhelm, Jens; Fischer, Susan; Tatagiba, Marcos; Nagel, Christoph; Jeibmann, Astrid; Bohring, Axel; Mautner, Victor-Felix; Paulus, Werner

    2012-05-01

    We analyzed the histologic features of peripheral nerve sheath tumors occurring in 14 patients with schwannomatosis. Among a total of 31 tumors, 19 tumors (61%) showed schwannoma-like nodules within a neurofibroma-like tumor, corresponding to hybrid neurofibroma/schwannoma. At least 1 hybrid tumor occurred in 10 of 14 (71%) schwannomatosis patients. We then retrieved cases of hybrid tumors without documented relation to schwannomatosis from our database and identified 41 tumors arising in 23 patients. More than half of these patients (14/23) were reported to suffer from multiple peripheral nerve sheath tumors, favoring a tumor syndrome. Indeed, analysis of clinical records revealed the diagnosis of neurofibromatosis type 2 (NF2) in 26% (6/23), neurofibromatosis type 1 (NF1) in 9% (2/23), definite schwannomatosis in 4% (1/23), and possible schwannomatosis in 13% (3/23) of patients with multiple nerve sheath tumors. Our findings suggest that hybrid neurofibroma/schwannoma represents a common tumor type in schwannomatosis and shows a striking association with neurofibromatoses.

  1. Tumor del cuerpo calloso como presentación de neurofibromatosis tipo 1 en un paciente y revisión de la bibliografía

    OpenAIRE

    Pascual-Castroviejo, Ignacio; Pascual Pascual, Samuel Ignacio; Velázquez-Fragua, Ramón; Viaño, Juan

    2012-01-01

    Introducción. La neurofibromatosis tipo 1 (NF1) es uno de los síndromes neurocutáneos más frecuentes y puede asociarse a tumores intracraneales en cualquier localización, pero excepcionalmente en el cuerpo calloso. Objetivos. Presentar un caso de NF1 que se manifiesta como un tumor de cuerpo calloso y llevar a cabo una revisión de la incidencia de tumores del cuerpo calloso en nuestra casuística y en la bibliografía. Caso clínico. Niño visto desde los 3 años con criterios diagnóst...

  2. Ⅰ型神经纤维瘤病的治疗进展%Progress in Treatment of Neurofibromatosis Type 1

    Institute of Scientific and Technical Information of China (English)

    高阳(综述); 胡晓洁; 林晓曦(审校)

    2014-01-01

    Ⅰ型神经纤维瘤病(NF1)是一种常染色体显性遗传病,可引起皮肤、骨骼、脏器等的损伤和功能障碍,治疗困难。本文主要对现有的NF1的各种治疗方法的适应证,治疗过程中的注意事项,以及今后可能的发展方向进行综述。%Neurofibromatosis type 1 is an autosomal dominant genetic disease, and can cause multisystem disorders affecting skin, bone, vision and internal organs. It is difficult to cure. In this paper, the indications, therapy attentions and development direction of different treatment methods were summarized.

  3. Hydrocephalus following bilateral dumbbell-shaped c2 spinal neurofibromas resection and postoperative cervical pseudomeningocele in a patient with neurofibromatosis type 1: a case report.

    Science.gov (United States)

    Montemurro, Nicola; Cocciaro, Ardico; Meola, Antonio; Lutzemberger, Ludovico; Vannozzi, Riccardo

    2014-10-01

    Study Design Case report. Objective To present a rare case of hydrocephalus following bilateral dumbbell-shaped C2 spinal neurofibromas resection and postoperative cervical pseudomeningocele in a patient with neurofibromatosis type 1 (NF1). Methods The patient's clinical course is retrospectively reviewed. A 37-year-old man affected by NF1 referred to our department for progressive weakness of both lower extremities and gait disturbance. Radiological imaging showed bilateral dumbbell-shaped C2 spinal neurofibromas. After its resection, at the 1-month follow-up evaluation, the patient reported headache and nausea. A CT brain scan showed a postoperative cervical pseudomeningocele and an increase in the ventricular sizes, resulting in hydrocephalus. Results A ventriculoperitoneal shunting was performed using a programmable valve opening pressure set to 120 mmH20. After surgery, the patient's neurological status markedly improved. Conclusion Hydrocephalus must be considered a possible complication of cervical spine tumor resection.

  4. DIFFERENCES IN FUNCTION BETWEEN NEUROFIBROMATOSIS PATIENTS OSTEOCLAST AND HEALTHY PEOPLE%神经纤维瘤病患者与健康人破骨细胞机能的差异性研究

    Institute of Scientific and Technical Information of China (English)

    郑颖; 余华; 李会杰; 刘亚玲; 张奇; 闫金成

    2013-01-01

    目的 目的 探讨神经纤维瘤病(neurofibromatosis type 1,NF1)患者和正常人外周血来源的破骨细胞的形成、游走,骨表面附着和骨吸收功能,以及蛋白激酶B(protein kinase B,Akt)、细胞外调节蛋白激酶(extracellular signal-regulated kinase,Erk)、Rac1活化的不同.方法 分离NF1患者和正常人外周血单个核细胞,细胞因子作用下分化为破骨细胞,然后观察破骨细胞的形成、游走,骨表面附着和骨吸收功能,并且用Western-Blot方法比较2组标本在巨噬细胞集落刺激因子(macrophase colony-stimulating factor,M-CSF)刺激后Akt、Erk以及Rac1的活化情况.结果 NF1患者破骨细胞前驱细胞的数量为正常对照组的2倍.在破骨细胞形成试验中,NF1患者破骨细胞的形成显著高于正常对照组.NF1破骨细胞增殖显著高于正常对照组.NF1患者破骨细胞游走能力较正常对照组明显增加.NF1患者的骨吸收显著高于正常对照组.NF1患者破骨细胞Actin环形成显著高于正常对组.与正常对照相比,NF1患者破骨细胞活性Akt和活性Erk水平显著增高.NF1患者Rac1活性显著增高.结论 NF1患者的破骨细胞前驱细胞功能增强(包括移动功能、附着功能和骨吸收功能),在M-CSF刺激下,Akt和Erk活化水平增强,NF1患者破骨细胞中Rac1-GTPase活化增加.

  5. Tumor segmentation of whole-body magnetic resonance imaging in neurofibromatosis type 1 patients: tumor burden correlates

    Energy Technology Data Exchange (ETDEWEB)

    Heffler, Michael A.; Xi, Yin; Chhabra, Avneesh [University of Texas Southwestern Medical Center, Department of Radiology, Dallas, TX (United States); Le, Lu Q. [University of Texas Southwestern Medical Center, Department of Dermatology, Dallas, TX (United States)

    2017-01-15

    Segmentation of whole-body MRI (WBMRI) to assess the feasibility, quantitate the total tumor volume (tumor burden) in patients with neurofibromatosis type 1 (NF1) and examine associations with demographic, disease-related and anthropomorphic features. A consecutive series of patients with NF1 underwent WBMRI and were reviewed for tumors. Tumors were segmented using a semiautomated software-based tool. Tumors were classified as superficial or deep and discrete or plexiform. Segmentation times were recorded. Segmentation yielded the quantity and tumor burden of superficial, internal and plexiform tumors. Correlations between segmentation data and demographic, disease-related and anthropomorphic features were examined. Fifteen patients were evaluated (42.3 ± 13.6 years, 10 female, 5 male). Segmentation times were a median of 30 min and yielded 2,328 tumors (1,582 superficial, 746 internal and 23 plexiform). One tumor was malignant. Tumor counts ranged from 14 to 397. Tumor burden ranged from 6.95 cm3 to 571 cm3. Individual tumor volume ranged from 0.0120 cm3 to 298 cm3. Significant correlation was found between the total volume of superficial tumors and height (ρ = 0.5966, p < 0.02). Male patients had higher overall tumor burdens (p < 0.05) and higher superficial tumor burden (p < 0.03). Patients with negative family history had more tumors (p < 0.05). Segmentation of WBMRI in patients with NF1 is feasible and elucidates meaningful relationships among disease phenotype, anthropomorphic and demographic features. (orig.)

  6. Multimodal imaging in neurofibromatosis type 1-associated nerve sheath tumors; Multimodale Bildgebung bei Neurofibromatose-Typ-1-assoziierten Nervenscheidentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Salamon, J.; Adam, G. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Mautner, V.F. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Neurology; Derlin, T. [Hannover Medical School, Hannover (Germany). Dept. of Nuclear Medicine

    2015-12-15

    Neurofibromatosis type 1 (NF1) is a neurogenetic disorder. Individuals with NF1 may develop a variety of benign and malignant tumors of which peripheral nerve sheath tumors represent the most frequent entity. Plexiform neurofibromas may demonstrate a locally destructive growth pattern, may cause severe symptoms and may undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs). Whole-body magnetic resonance imaging (MRI) represents the reference standard for detection of soft tissue tumors in NF1. It allows for identification of individuals with plexiform neurofibromas, for assessment of local tumor extent, and for evaluation of whole-body tumor burden on T2-weighted imaging. Multiparametric MRI may provide a comprehensive characterization of different tissue properties of peripheral nerve sheath tumors, and may identify parameters associated with malignant transformation. Due to the absence of any radiation exposure, whole-body MRI may be used for serial follow-up of individuals with plexiform neurofibromas. {sup 18}F-fluorodeoxyglucose positron-emission-tomography (FDG PET/CT) allows a highly sensitive and specific detection of MPNST, and should be used in case of potential malignant transformation of a peripheral nerve sheath tumor. PET/CT provides a sensitive whole-body tumor staging. The use of contrast-enhanced CT for diagnosis of peripheral nerve sheath tumors is limited to special indications. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of peripheral nerve sheath tumors are required.

  7. Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma

    Energy Technology Data Exchange (ETDEWEB)

    Mautner, V.F. [Department of Neurology, Klinikum Nord Hamburg, Langenhorner Chaussee 560, 22419, Hamburg (Germany); Friedrich, R.E. [Department of Maxillofacial Surgery, Universitaetsklinikum Eppendorf, Hamburg (Germany); Deimling, A. von [Department of Neuropathology, Charite, Berlin (Germany); Hagel, C. [Department of Neuropathology, Universitaetsklinikum Eppendorf, Hamburg (Germany); Korf, B. [Center for Human Genetics, Harvard Institutes of Medicine, Boston, MA (United States); Knoefel, M.T. [Department of Surgery, Universitaetsklinikum Eppendorf, Hamburg (Germany); Wenzel, R.; Fuensterer, C. [MRI-Institute Hamburg Othmarschen, Hamburg (Germany)

    2003-09-01

    Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve-sheath tumours (MPNST), usually arising from PNF, and this is the major cause of poor survival. A better prognosis can be achieved if the tumours are diagnosed at an early stage. Our objective was to establish MRI criteria for MPNST and to test their usefulness in detecting early malignant change in PNF. MRI was performed on 50 patients with NF1 and nerve-sheath tumours, of whom seven had atypical pain, tumour growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI all seven symptomatic patients had inhomogeneous lesions, due to necrosis and haemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumours with inhomogeneous areas in addition to central lesions did not allow exclusion of malignancy. Only three of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumours being of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All three asymptomatic patients with inhomogeneous lesions were shown to have MPNST. (orig.)

  8. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes.

    Science.gov (United States)

    Lodish, Maya B; Stratakis, Constantine A

    2010-06-01

    Neurofibromatosis type 1 (NF-1) and tuberous sclerosis complex (TSC) are two familial syndromes known as phakomatoses that may be associated with endocrine tumours. These hereditary cutaneous conditions affect the central nervous system and are characterised by the development of hamartomas. Over the past 20 years, there have been major advances in our understanding of the molecular basis of these diseases. Both NF-1 and TSC are disorders of unregulated progression through the cell cycle, in which causative genes behave as tumour suppressor genes. The pathogenesis of these familial syndromes is linked by the shared regulation of a common pathway, the protein kinase mammalian target of rapamycin (mTOR). Additional related disorders that also converge on the mTOR pathway include Peutz-Jeghers syndrome and Cowden syndrome. All of these inherited cancer syndromes are associated with characteristic skin findings that offer a clue to their recognition and treatment. The discovery of mTOR inhibitors has led to a possible new therapeutic modality for patients with endocrine tumours as part of these familial syndromes.

  9. Lymphangiopathy in neurofibromatosis 1 manifesting with chylothorax, pericardial effusion, and leg edema

    Directory of Open Access Journals (Sweden)

    Finsterer J

    2013-09-01

    Full Text Available Josef Finsterer,1 Claudia Stollberger,2 Elisabeth Stubenberger,3 Sasan Tschakoschian4 1Krankenanstalt Rudolfstiftung, Vienna, Austria; 2Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria; 3Thoracic Surgery Department, Vienna, Austria; 4Interne Lungenabt, Vienna, Austria Background: This case report documents the affliction of the lymph vessels as a phenotypic feature of neurofibromatosis-1 (NF-1. Methodology: Routine transthoracic echocardiography, computed tomography scan of the thorax, magnetic resonance angiography of the renal arteries, and conventional digital subtraction angiography were applied. Comprehensive NF-1 mutation analysis was carried out by fluorescence in situ hybridization analysis, long-range reverse transcriptase polymerase chain reaction, and multiple-ligation probe assay. All other investigations were performed using routine, well-established techniques. Results: The subject is a 34-year-old, half-Chinese male; NF-1 was suspected at age 15 years for the first time. His medical history included preterm birth, mild facial dysmorphism, "café au lait" spots, subcutaneous and paravertebral fibromas, multifocal tachycardia, atrial fibrillation, and heart failure in early infancy. Noncalcified bone fibromas in the femur and tibia were detected at age 8 years. Surgical right leg lengthening was carried out at age 11 years. Bilateral renal artery stenosis, stenosis and aneurysm of the superior mesenteric artery, and an infrarenal aortic stenosis were detected at age 15 years. Leg edema and ectasia of the basilar artery were diagnosed at age 18 years. After an episode with an erysipela at age 34 years, he developed pericardial and pleural effusion during a 4-month period. Stenosis of the left subclavian vein at the level of thoracic duct insertion was detected. After repeated pleural punctures, pleural effusion was interpreted as chylothorax. Reduction of lymph fluid production by diet and injection of talcum into

  10. Outcomes of Spinal Fusion for Cervical Kyphosis in Children with Neurofibromatosis.

    Science.gov (United States)

    Helenius, Ilkka J; Sponseller, Paul D; Mackenzie, William; Odent, Thierry; Dormans, John P; Asghar, Jahangir; Rathjen, Karl; Pahys, Joshua M; Miyanji, Firoz; Hedequist, Daniel; Phillips, Jonathan H

    2016-11-02

    Cervical kyphosis may occur with neurofibromatosis type I (NF1) and is often associated with vertebral dysplasia. Outcomes of cervical spinal fusion in patients with NF1 are not well described because of the rarity of the condition. We aimed to (1) characterize the clinical presentation of cervical kyphosis and (2) report the outcomes of posterior and anteroposterior cervical fusion for the condition in these children. The medical records and imaging studies of 22 children with NF1 who had undergone spinal fusion for cervical kyphosis (mean, 67°) at a mean age of 11 years and who had been followed for a minimum of 2 years were reviewed. Thirteen children presented with neck pain; 10, with head tilt; 9, with a previous cervical laminectomy or fusion; and 5, with a neurologic deficit. Two patients had spontaneous dislocation of the mid-cervical spine without a neurologic deficit. Eleven had scoliosis, with the major curve measuring a mean of 61°. Nine patients underwent posterior and 13 underwent anteroposterior surgery. Twenty-one received spinal instrumentation, and 1 was not treated with instrumentation. Preoperative halo traction was used for 9 patients, and it reduced the mean preoperative kyphosis by 34% (p = 0.0059). At the time of final follow-up, all spinal fusion sites had healed and the cervical kyphosis averaged 21° (mean correction, 69%; p < 0.001). The cervical kyphosis correction was significantly better after the anteroposterior procedures (83%) than after the posterior-only procedures (58%) (p = 0.031). Vertebral dysplasia and erosion continued in all 17 patients who had presented with dysplasia preoperatively. Thirteen patients had complications, including 5 new neurologic deficits and 8 cases of junctional kyphosis. Nine patients required revision surgery. Junctional kyphosis was more common in children in whom ≤5 levels had been fused (p = 0.054). Anteroposterior surgery provided better correction of cervical kyphosis than posterior spinal

  11. NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics.

    Science.gov (United States)

    Cirenajwis, Helena; Lauss, Martin; Ekedahl, Henrik; Törngren, Therese; Kvist, Anders; Saal, Lao H; Olsson, Håkan; Staaf, Johan; Carneiro, Ana; Ingvar, Christian; Harbst, Katja; Hayward, Nicholas K; Jönsson, Göran

    2017-03-07

    In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

  12. Analysis report of four patients with Neurofibromatosis type 1 from a family%Ⅰ型神经纤维瘤一家系4例的分析报告

    Institute of Scientific and Technical Information of China (English)

    周琴; 彭忠禄; 陈莹花; 刘晶; 雷日华; 张贵平; 肖毅仁; 罗桐秀

    2012-01-01

    目的 分析一个面部有巨大神经纤维瘤家系的临床表现及遗传方式.方法 根据美国国立卫生研究院(NIH)提出的神经纤维瘤诊断标准进行诊断,通过染色体检查和家系分析方法确定遗传方式.结果 家系12名成员中有3名患者表现出Ⅰ型神经纤维瘤的4项临床特征,染色体检查无异常,家系分析表现出常染色体显性遗传特点.结论 该家系为Ⅰ型神经纤维瘤家系,遗传方式为常染色体显性遗传.%Objective To confirm the hereditary mode and the clinical manifestations of a Neurofibromatosis family where a patient develops a huge plexiform neurofibroma on the face. Methods The clinical manifestations was checked based on the standard diagnostic criteria for NF1 issued by National Institute of Health (NIH) in 1988, then the pedigree analysis and chromosome examination were carried out. Results Four clinical features of Neurofibromatosis type 1 ( NF1) was shown in three of the seven members in the family. The chromosome phenotype is normal, but Pedigree analysis showed that NF1 in this family meets autosomal dominant features. Conclusions Neurofibromatosis in this family is a NF1 family,and is an autosomal dominant inherited disease.

  13. Development of the pediatric quality of life inventory neurofibromatosis type 1 module items for children, adolescents and young adults: qualitative methods.

    Science.gov (United States)

    Nutakki, Kavitha; Varni, James W; Steinbrenner, Sheila; Draucker, Claire B; Swigonski, Nancy L

    2017-01-11

    Health-related quality of life (HRQOL) is arguably one of the most important measures in evaluating effectiveness of clinical treatments. At present, there is no disease-specific outcome measure to assess the HRQOL of children, adolescents and young adults with Neurofibromatosis Type 1 (NF1). This study aimed to develop the items and support the content validity for the Pediatric Quality of Life Inventory™ (PedsQL™) NF1 Module for children, adolescents and young adults. The iterative process included multiphase qualitative methods including a literature review, survey of expert opinions, semi-structured interviews, cognitive interviews and pilot testing. Fifteen domains were derived from the qualitative methods, with content saturation achieved, resulting in 115 items. The domains include skin, pain, pain impact, pain management, cognitive functioning, speech, fine motor, balance, vision, perceived physical appearance, communication, worry, treatment, medicines and gastrointestinal symptoms. This study is limited because all participants are recruited from a single-site. Qualitative methods support the content validity for the PedsQL™ NF1 Module for children, adolescents and young adults. The PedsQL™ NF1 Module is now undergoing national multisite field testing for the psychometric validation of the instrument development.

  14. A rare case of segmental neurofibromatosis involving the sciatic nerve.

    Science.gov (United States)

    Trocchia, Aron; Reyes, Alma; Wilson, Jon; Les, Kimberly

    2010-05-01

    Segmental neurofibromatosis (NF-5) is an extremely rare variant of neurofibromatosis involving a single extremity without pathologic features beyond the midline. A case of segmental neurofibromatosis involving the sciatic nerve and its branches is presented with a detailed description of the patient's preoperative findings plus postoperative course through 1-year follow-up. Clinical, histologic, and genetic findings are given along with a brief review of the literature on segmental neurofibromatosis. Last, treatment options and postoperative care recommendations are provided.

  15. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden.

    Science.gov (United States)

    Johansson, Gunnar; Peng, Po-Chun; Huang, Po-Yuan; Chien, Hsiung-Fei; Hua, Kuo-Tai; Kuo, Min-Liang; Chen, Chin-Tin; Lee, Ming-Jen

    2014-01-01

    Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

  16. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden.

    Directory of Open Access Journals (Sweden)

    Gunnar Johansson

    Full Text Available Neurofibromatosis type 1 (NF1 is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas and malignant peripheral nerve sheath tumors (MPNST. The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

  17. Magnetization transfer ratio and volumetric analysis of the brain in macrocephalic patients with neurofibromatosis type 1

    Energy Technology Data Exchange (ETDEWEB)

    Margariti, Persefoni N.; Katzioti, Frosso G.; Zikou, Anastasia K.; Argyropoulou, Maria I. [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); Blekas, Konstantinos [University of Ioannina, Department of Computer Science, Ioannina (Greece); Tzoufi, Meropi [University of Ioannina, Child Health Department, Medical School, Ioannina (Greece)

    2007-02-15

    The purpose of the study was to evaluate brain myelination by measuring the magnetization transfer ratio (MTR) and to measure grey (GMV) and white matter volume (WMV) in macrocephalic children with neurofibromatosis type 1 (NF1). Seven NF1 patients (aged 0.65-16.67 years) and seven age- and gender-matched controls were studied. A three-dimensional (3D) gradient echo sequence with and without magnetization transfer (MT) prepulse was used for MTR assessment. Volume measurements of GM and WM were performed by applying segmentation techniques on T2-weighted turbo spin echo images (T2WI). MTR of unidentified bright objects (UBOs) on T2WI in cerebellar white matter (52.8{+-}3.3), cerebral peduncles (48.5{+-}1.5), hippocampus (52.6{+-}1.1), internal capsule (55.7{+-}0.3), globus pallidus (52.7{+-}3.9), and periventricular white matter (52.6{+-}1.2) was lower than in the corresponding areas of controls (64.6{+-}2.5, 60.8{+-}1.3, 56.4{+-}0.9, 64.7{+-}1.9, 59.2{+-}2.3, 63.6{+-}1.7, respectively; p<0.05). MTR of normal-appearing brain tissue in patients was not significantly different than in controls. Surface area (mm{sup 2}) of the corpus callosum (809.1{+-}62.8), GMV (cm{sup 3}) (850.7{+-}42.9), and white matter volume (WMV) (cm{sup 3}) (785.1{+-}85.2) were greater in patients than in controls (652.5{+-}52.6 mm{sup 2}, 611.2{+-}92.1 cm{sup 3}, 622.5{+-}108.7 cm{sup 3}, respectively; p<0.05). To conclude, macrocephaly in NF1 patients is related to increased GMV and WMV and corpus callosum enlargement. MTR of UBOs is lower than that of normal brain tissue. (orig.)

  18. Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis.

    Science.gov (United States)

    Smith, Miriam J; Esparza, Sonia; Merker, Vanessa L; Muzikansky, Alona; Bredella, Miriam A; Harris, Gordon J; Kassarjian, Ara; Cai, Wenli; Walker, James A; Mautner, Victor F; Plotkin, Scott R

    2013-05-01

    Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are characterized by a predisposition to develop multiple neurofibromas and schwannomas. Currently, there is no blood test to estimate tumor burden in patients with these disorders. We explored whether S100β would act as a biomarker of tumor burden in NF since S100β is a classic immunohistochemical marker of astrocytes, oligodendrocytes and Schwann cells and a small study showed S100β concentrations correlate with the volume of vestibular schwannomas. We calculated whole-body tumor burden in subjects with NF1, NF2, and schwannomatosis using whole-body MRI (WBMRI) and measured the concentration of S100β in plasma using ELISA. We used chi-square tests and Spearman rank correlations to test the relationship between S100β levels and whole-body tumor burden. 127 consecutive patients were enrolled in the study (69 NF1 patients, 28 NF2 patients, and 30 schwannomatosis patients). The median age was 40years, 43% were male, and median whole-body tumor volume was 26.9mL. There was no relationship between the presence of internal tumors and the presence of detectable S100β in blood for the overall group or for individual diagnoses (p>0.05 by chi-square for all comparisons). Similarly, there was no correlation between whole-body tumor volume and S100β concentration for the overall group or for individual diagnoses (p>0.05 by Spearman for all comparisons). Plasma S100β is not a useful biomarker for tumor burden in the neurofibromatoses. Further work is needed to identify a reliable biomarker of tumor burden in NF patients. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  19. Facing Neurofibromatosis: A Guide for Teens

    Science.gov (United States)

    ... well, talk with your NF specialist. Learning difficulties Learning disabilities affect 50 percent of people with NF1. It’s ... to be embarrassed or ashamed of – having a learning disability does not make you less smart. We all ...

  20. The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion.

    Directory of Open Access Journals (Sweden)

    Katharina Wimmer

    2011-11-01

    Full Text Available Long interspersed (L1 and Alu elements are actively amplified in the human genome through retrotransposition of their RNA intermediates by the -100 still retrotranspositionally fully competent L1 elements. Retrotransposition can cause inherited disease if such an element is inserted near or within a functional gene. Using direct cDNA sequencing as the primary assay for comprehensive NF1 mutation analysis, we uncovered in 18 unrelated index patients splicing alterations not readily explained at the genomic level by an underlying point-mutation or deletion. Improved PCR protocols avoiding allelic drop-out of the mutant alleles uncovered insertions of fourteen Alu elements, three L1 elements, and one poly(T stretch to cause these splicing defects. Taken together, the 18 pathogenic L1 endonuclease-mediated de novo insertions represent the largest number of this type of mutations characterized in a single human gene. Our findings show that retrotransposon insertions account for as many as -0.4% of all NF1 mutations. Since altered splicing was the main effect of the inserted elements, the current finding was facilitated by the use of RNA-based mutation analysis protocols, resulting in improved detection compared to gDNA-based approaches. Six different insertions clustered in a relatively small 1.5-kb region (NF1 exons 21(16-23(18 within the 280-kb NF1 gene. Furthermore, three different specific integration sites, one of them located in this cluster region, were each used twice, i.e. NM_000267.3(NF1:c.1642-1_1642 in intron 14(10c, NM_000267.3(NF1:c.2835_2836 in exon 21(16, and NM_000267.3(NF1:c.4319_4320 in exon 33(25. Identification of three loci that each served twice as integration site for independent retrotransposition events as well as 1.5-kb cluster region harboring six independent insertions supports the notion of non-random insertion of retrotransposons in the human genome. Currently, little is known about which features make sites

  1. Neurofibromatosis

    Science.gov (United States)

    ... Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  2. Neurofibromatosis

    Science.gov (United States)

    ... Corneal Abrasions Dilating Eye Drops Lazy eye (defined) Pink eye (defined) Retinopathy of Prematurity Strabismus Stye (defined) Vision ... Corneal Abrasions Dilating Eye Drops Lazy eye (defined) Pink eye (defined) Retinopathy of Prematurity Strabismus Stye (defined) Vision ...

  3. Adrenal incidentaloma in neurofibromatosis type 1

    Directory of Open Access Journals (Sweden)

    Tančić-Gajić Milina

    2008-01-01

    Full Text Available INTRODUCTION Neurofibromatosis type 1 is one of the most common genetically transmitted diseases with a high index of spontaneous mutations and extremely varied and unpredictable clinical manifestations. It is diagnosed by the existence of certain clinical criteria. The presence of numerous localised cutaneous neurofibromas or a plexiform neurofibroma is virtually pathognomonic of neurofibromatosis type 1. The incidence of pheochromocytoma in neurofibromatosis type 1 is 0.1-5.7%. CASE OUTLINE A 56-year old female patient was admitted for further evaluation of incidental adrenal tumour previously diagnosed on computerized tomography (CT. She had previously unrecognized neurofibromatosis type 1 and a clinical picture which could remind of pheochromocytoma. None of the catecholamine samples in 24 hr urine indicated functionally active pheochromocytoma. Chromogranin A was moderately increased. Decision for operation was made after performing the image techniques. Adrenal incidentaloma had features of pheochromocytoma on abdominal magnetic resonance imaging (MRI, with positive 131I-MIBG (iodine 131-labelled metaiodobenzylguanidine scintigraphy. After being treated with phenoxybenzamine and propranolol, she was operated on. The pathohistological finding showed the case of left adrenal pheochromocytoma. CONCLUSION Detailed diagnostic procedure for pheochromocytoma should be performed with patients having neurofibromatosis type 1 and adrenal incidentaloma. Pheochromocytomas are rare tumours with fatal outcome if not duly recognized and cured.

  4. Proton MR spectroscopic imaging of basal ganglia and thalamus in neurofibromatosis type 1: correlation with T2 hyperintensities

    Energy Technology Data Exchange (ETDEWEB)

    Barbier, Charlotte; Barantin, Laurent [CHRU and Tours University, Department of Neuroradiology, Tours (France); Chabernaud, Camille [CHRU and Tours University et INSERM U930, Department of Pediatric Neurology, Tours (France); Bertrand, Philippe [CHRU and Tours University, Department of Radiology, Tours (France); Sembely, Catherine; Sirinelli, Dominique [CHRU and Tours University, Department of Pediatric Radiology, Tours (France); Castelnau, Pierre [CHRU and Tours University et INSERM U930, Department of Pediatric Neurology, Tours (France); CHRU and Tours University et INSERM U930, Tours (France); Neurologie Pediatrique and INSERM U930, Hopital d' Enfants Gatien de Clocheville, Tours cedex 09 (France); Cottier, Jean-Philippe [CHRU and Tours University, Department of Neuroradiology, Tours (France); CHRU and Tours University et INSERM U930, Tours (France)

    2011-02-15

    Neurofibromatosis type 1 (NF1) is frequently associated with hyperintense lesions on T2-weighted images called ''unidentified bright objects'' (UBO). To better characterize the functional significance of UBO, we investigate the basal ganglia and thalamus using spectroscopic imaging in children with NF1 and compare the results to anomalies observed on T2-weighted images. Magnetic resonance (MR) data of 25 children with NF1 were analyzed. On the basis of T2-weighted images analysis, two groups were identified: one with normal MR imaging (UBO- group; n = 10) and one with UBO (UBO+ group; n = 15). Within the UBO+ group, a subpopulation of patients (n = 5) only had lesions of the basal ganglia. We analyzed herein seven regions of interest (ROIs) for each side: caudate nucleus, capsulo-lenticular region, lateral and posterior thalamus, thalamus (lateral and posterior voxels combined), putamen, and striatum. For each ROI, a spectrum of the metabolites and their ratio was obtained. Patients with abnormalities on T2-weighted images had significantly lower NAA/Cr, NAA/Cho, and NAA/mI ratios in the lateral right thalamus compared with patients with normal T2. These abnormal spectroscopic findings were not observed in capsulo-lenticular regions that had UBO but in the thalamus region that was devoid of UBO. Multivoxel spectroscopic imaging using short-time echo showed spectroscopic abnormalities in the right thalamus of NF1 patients harboring UBO, which were mainly located in the basal ganglia. This finding could reflect the anatomical and functional interactions of these regions. (orig.)

  5. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve.

    Science.gov (United States)

    Ribeiro, Sara; Napoli, Ilaria; White, Ian J; Parrinello, Simona; Flanagan, Adrienne M; Suter, Ueli; Parada, Luis F; Lloyd, Alison C

    2013-10-17

    Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1(-/-) mSCs redifferentiate normally, whereas at the wound site Nf1(-/-) mSCs give rise to neurofibromas in both Nf1(+/+) and Nf1(+/-) backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  6. Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve

    Directory of Open Access Journals (Sweden)

    Sara Ribeiro

    2013-10-01

    Full Text Available Schwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

  7. Neurofibromatosis tipo I: Mutación de splicing detectada por MLPA y secuenciación en la Argentina

    Directory of Open Access Journals (Sweden)

    Sergio Laurito

    2015-04-01

    Full Text Available La neurofibromatosis tipo 1 (NF1 es un desorden genético autosómico dominante, con una prevalencia de 1 en 2500-3000 nacidos vivos. La dificultad diagnóstica se debe al tamaño extenso del gen NF1 con pocos sitios hot-spot, la ausencia de una clara relación genotipo-fenotipo y rasgos clínicos con un espectro muy heterogéneo. Un caso sospechoso de NF1 procedente de la provincia de Jujuy fue analizado por MLPA (multiplex ligation-dependent probe amplification en nuestro laboratorio. Mujer, adolescente mestiza (Amerindia/Europea, con un osteoma maxilar, lordosis lumbar, neurofibromas cutáneos y manchas café con leche. Por MLPA se detectó una alteración en el exón 13 del gen NF1. Por secuenciación del exón 13 se identificó una mutación "missense" en la posición 1466 del ARNm (NM_000267.3:c.1466A>G que introduce un sitio de splicing aberrante. La patogenicidad de la mutación fue corroborada en la base de datos de variantes clínicas del National Center for Biotechnology Information. En nuestro conocimiento, este es el primer registro de una mutación NF1 en un paciente proveniente de poblaciones mestizas del Noroeste Argentino. La alteración ha sido reportada en individuos de otras poblaciones de origen muy disímil al del caso presentado, como la europea, sugiriendo que el sitio podría considerarse un sitio hot-spot del gen. Donde exista baja disponibilidad de diagnósticos moleculares, como en nuestro caso, se puede aplicar un algoritmo que comience por el estudio del gen NF1 por MLPA, metodología relativamente sencilla y de costo accesible. Con ella se evita enviar muestras al extranjero para análisis genéticos.

  8. 中国人NF1基因突变分析%Study on mutations of NF1 gene in Chinese

    Institute of Scientific and Technical Information of China (English)

    孙漓; 周列民; 周珏倩; 刘焯霖; 宁玉萍

    2007-01-01

    目的 通过对28个家系56例Ⅰ型神经纤维瘤病患者NF1-GRD相邻外显子进行突变检测,探讨和分析中国人NF1基因的突变规律、突变类型、机制以及与临床表型的相关性,以期发现潜在的突变热点.方法 采用聚合酶链反应-单链构象多态性和(或)异源双链分析(SSCP/HA)技术,结合DNA测序方法,对56例Ⅰ型神经纤维瘤病患者的NF1基因第20、28、29、39号外显子的突变或多态性进行筛查.结果 在所检测的28个家系中有一家系父子3例Ⅰ型神经纤维瘤病患者的NF1基因第20号外显子均出现异常移动的电泳条带,重复检测单链构象多态实验无异常发现,而异源双链实验则仍显示有1条移动异常的双链电泳条带,DNA测序证实为该家系第20号外显子上T→G的杂合性突变,即Leu1141Arg错义突变.同时发现,另1例Ⅰ型神经纤维瘤病患者的第28号外显子亦表现为电泳条带移动异常,测序证实为第28号外显子5'端上游第28位核苷酸G→T杂合子.未发现第29号和39号外显子电泳条带移动异常.结论 聚合酶链反应-单链构象多态性与异源双链分析联合应用,可提高Ⅰ型神经纤维瘤病基因突变检测的敏感性和阳性检出率.所测28个家系56例患者NF1基因的第20、28、29及39号外显子并非突变热点或突变率相对较高的区域.

  9. Radiosurgery for type II neurofibromatosis.

    Science.gov (United States)

    Rowe, Jeremy; Radatz, Matthias; Kemeny, Andras

    2008-01-01

    A summary of our radiosurgical experience treating type II neurofibromatosis (NF2) vestibular schwannomas (VSs), based on a retrospective consecutive series of 122 tumours in 92 patients, with an extended series of a further 22 patients (906 patient-years of follow-up) to investigate the risk of malignancy after radiosurgery. With current techniques, we estimate that 8 years after radiosurgery for NF2 VS, 20% of patients will have required further treatment, 50% will be well controlled, and in 30% there will have been some concern about control, but they will have been managed conservatively. Three years after treatment, approximately 40% retain their functional hearing, 40% have some deterioration, 20% becoming deaf in that ear. The risk of facial palsy was 5%. Two malignancies were recorded after radiosurgery, in one the malignant behaviour preceded treatment. This is less than the previously reported rate of spontaneously developing malignant gliomas in NF2. Whilst the clinical results are far worse than those achieved treating sporadic tumours, this applies equally to the results of surgery or observation when treating NF2 tumours. It is important therefore that these patients are given advice specific for NF2. Considering this, we believe that radiosurgery remains a valuable minimally invasive treatment option for selected NF2 patients.

  10. 眼眶Ⅰ型神经纤维瘤颅眶骨异常的CT征%Cranio-Orbital Abnormalities in Orbital Neurofibromatosis Type Ⅰ

    Institute of Scientific and Technical Information of China (English)

    高文; 朱利民; 何彦津; 林婷婷; 张薇; 孙世振

    2010-01-01

    目的 探讨眼眶Ⅰ型神经纤维瘤(NF-1)颅眶骨异常的CT表现及机制.方法 2008年1月至2010年1月收治的7例眼眶NF-1患者中5例存在颅眶骨改变,分析该5例患者的临床资料和CT表现,全部病例均经手术病理和(或)临床证实.结果 5例眼眶NF-1中3例为颅眶沟通肿瘤(其中1例伴有上睑额部肿瘤),2例为上睑、颞、额部肿瘤.全部存在不同程度的颅眶骨异常,主要表现:蝶骨大翼缺失5例,眶上裂增大5例,眶壁骨质缺失1例,蝶鞍变形1例,颞骨变形1例.另外,4例患者相应部位蛛网膜囊肿.结论 眼眶NF-1大部分存在不同程度的颅眶骨异常,以蝶骨大翼缺失最为显著.其发生机制复杂,可能同时存在先天发育异常和继发性改变,有待临床研究.%Objective To review the possible manifestation and mechanism of Cranio-Orbital Changes in Orbital Neurofibromatosis Type Ⅰ (NF-1). Methods The CT imaging abnormalities of the orbit and cranium in 5 patients with Orbital NF-1 were reviewed retrospectively. Results Orbital and cranial abnormalities were documented in 5 patients including 3 cases of tumor in cranium-orbit and 2 cases of tumor in upper eyelid, tempora, and forehead. Five cases had defect of the greater sphenoid wings; 5 had expansion of the orbital foramen, the superior orbital fissure; 1 had epippium abnormality, 1 had temporal bone abnormality,1 had defect of wall of orbit. In addition, 4 cases of orbital and cranial abnormalities contiguous to the arachnoid cyst. Conclusions Patients with orbit NF-1, bony orbital and cranial changes occur frequently, and defects of the greater sphenoid wings can be explained by a congenital neuroectodermal and mesodermal maldevelopment hypothesis. In addition, the orbital NF-1 mass and arachnoid cyst is associated with orbital and cranial abnormalities.

  11. Treatment of dystrophic scoliosis in neurofibromatosis Type 1 with one-stage posterior pedicle screw technique.

    Science.gov (United States)

    Wang, Zhenyu; Fu, Changfeng; Leng, Jiali; Qu, Zhigang; Xu, Feng; Liu, Yi

    2015-04-01

    Corrective surgery for dystrophic scoliosis in neurofibromatosis Type 1 (NF-1) is challenging. There are various surgical methods, all with unsatisfactory outcomes. The purpose of the study was to evaluate the clinical outcomes of the treatment of dystrophic scoliosis in NF-1 with one-stage posterior pedicle screw approach. This is a retrospective clinical study. Sixteen patients with dystrophic scoliosis in NF-1 underwent one-stage posterior surgery with pedicle screw system. We used preoperative and postoperative whole-spine radiographs to determine coronal and sagittal Cobb angles (curve correction); distance between apex vertebra and central sacral vertical line (DAC), pelvic obliquity, and shoulder tilt (coronal balance improvement); and sagittal vertical axis and pelvic tilt angle (sagittal balance improvement). We assessed the fusion rate using fusion segment computed tomography scan. Patients underwent surgery with or without osteotomy according to spinal flexibility. Fusion segment selection method of fusion segments selection which mean fusing from one or two levels proximal to upper end vertebra to one or two levels distal to the lower end vertebra (EV+1 or 2) or stable vertebrae fusion. There were no study-specific conflict of interest-associated biases. The average follow-up time was 40.9 months. Mean scoliosis and kyphosis improved from 83.2° to 27.6° and 58.5° to 26.8°, respectively; at the last follow-up, it was 30.4° and 27.4°, respectively. Mean DAC, pelvic obliquity, and shoulder tilt improved from 53.0 to 23.9, 8.1 to 4.9, and 9.8 to 7.5 mm, re