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Sample records for paciente con neurofibromatosis

  1. Neurofibromatosis

    PubMed Central

    Dooley, J.M.

    1987-01-01

    Neurofibromatosis is a common disorder that is inherited in an autosomal dominant fashion. It is now known that this disease occurs in two major forms: von Recklinghausen neurofibromatosis (VRNF), which used to be called `peripheral neurofibromatosis', typically presents with café-au-lait spots; and cutaneous neurofibromas. Many other manifestations of the disease are found, including skeletal deformities, central nervous-system tumours, hydrocephalus, and mental retardation or learning disabilities. The incidence of VRNF is 1/3000 live births, but 50% of patients represent new mutations. Bilateral acoustic neurofibromatosis (BANF) is less common than VRNF but is important because of the associated tumours on the 8th cranial nerve. The care of patients with either form of neurofibromatosis requires the skills of a physician who is aware of the potential complications and who is empathetic to the psychological stresses which accompany this disease. ImagesFigure 1Figure 2Figure 3 PMID:21263951

  2. Neurofibromatosis

    MedlinePlus

    ... There are three types of neurofibromatosis: Type 1 (NF1) causes skin changes and deformed bones. It usually ... symptoms. Genetic testing is also used to diagnose NF1 and NF2. There is no cure. Treatment can ...

  3. Neurofibromatosis.

    PubMed

    Korf, Bruce R

    2013-01-01

    The "neurofibromatoses" are a set of distinct genetic disorders that have in common the occurrence of tumors of the nerve sheath. They include NF1, NF2, and schwannomatosis. All are dominantly inherited with a high rate of new mutation and variable expression. NF1 includes effects on multiple systems of the body. The major NF1-associated tumor is the neurofibroma. In addition, clinical manifestations include bone dysplasia, learning disabilities, and an increased risk of malignancy. NF2 includes schwannomas of multiple cranial and spinal nerves, especially the vestibular nerve, as well as other tumors such as meningiomas and ependymomas. The schwannomatosis phenotype is limited to multiple schwannomas, and usually presents with pain. The genes that underlie each of the disorders are known: NF1 for neurofibromatosis type 1, NF2 for neurofibromatosis type 2, and INI1/SMARCB1 for schwannomatosis. Genetic testing is possible to identify mutations. Insights into pathogenesis are beginning to suggest new treatment strategies, and therapeutic trials with several new forms of treatment are underway.

  4. Neurofibromatosis 2

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000795.htm Neurofibromatosis 2 To use the sharing features on this page, please enable JavaScript. Neurofibromatosis 2 (NF2) is a disorder in which tumors form ...

  5. Neurofibromatosis Specialists

    MedlinePlus

    ... of Iowa Hospitals and Clinics Neurofibromatosis Clinic • Iowa City, IA Illinois Ann and Robert H. Lurie Children’s ... Sciences Center University of Oklahoma NF Clinic • Oklahoma City, OK Pennsylvania The Children’s Hospital of Philadelphia University ...

  6. Neurofibromatosis update.

    PubMed

    Crawford, Alvin H; Schorry, Elizabeth K

    2006-01-01

    Type 1 neurofibromatosis (NF-1), also known as von Recklinghausen disease, is one of the most common human single-gene disorders, affecting at least 1 million persons throughout the world. It encompasses a spectrum of multifacted disorders and may present with a wide range of clinical manifestations, including abnormalities of the skin, nervous tissue, bones, and soft tissues. The condition can be conclusively diagnosed when 2 of 7 criteria established by the National Institutes of Health Consensus Development Conference are met. Most children with NF-1 have no major orthopedic problems. For those with musculoskeletal involvement, the most important issue is early recognition. Spinal deformity, congenital tibial dysplasia (congenital bowing and pseudarthrosis), and disorders of excessive bone and soft-tissue growth are the three types of musculoskeletal manifestitations that require evaluation. Statistics gathered from the Cincinnati Children's Hospital Neurofibromatosis Center database of 588 patients show the incidence of spinal deformity in children with NF-1 to be 21%; pectus deformity, 4.3%; limb-length inequality, 7.1%; congenital tibial dysplasia, 5%; hemihypertrophy, 1.4%; and plexiform neurofibromas, 25%. The orthopedic complications can be managed, but only rarely are they cured. Current developments in molecular genetics are exciting and give hope to more positive outcomes.

  7. [Neurofibromatosis 2 (bilateral acoustic neurofibromatosis)].

    PubMed

    Yalcinkaya, C; Sarioglu, A; Boltshauser, E

    1989-10-14

    We report a personal series of 28 patients with neurofibromatosis 2 (NF-2), emphasizing the differences from classical NF-1. The hallmark of NF-2 is bilateral acoustic neuromas with initial symptoms usually occurring in the second or third decade. The natural history may lead to bilateral deafness, but hearing loss may also be a complication of surgery. NF-2 is frequently accompanied by additional intracranial tumors (particularly multiple meningiomas). Half of our patients had a spinal space-occupying lesion. NF-2 is inherited as an autosomal dominant trait, and many patients appear to represent new mutations.

  8. [Learning disorders in neurofibromatosis type 1].

    PubMed

    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.

  9. [Neurofibromatosis type 2 in childhood: a clinical characterization].

    PubMed

    Hinojosa-Mateo, C M; Reche-Sainz, J A; Hernandez-Nunez, A; Ramos-Lopez, M; Arpa-Fernandez, A; Natera-de Benito, D

    2017-02-01

    Introduccion. La neurofibromatosis de tipo 2 (NF2) es un trastorno neuroectodermico con patron de herencia autosomico dominante que condiciona una predisposicion para desarrollar tumores de varios tipos en el sistema nervioso central y periferico. Se asocia tambien con alteraciones oculares y cutaneas. Caso clinico. Varon de 12 años con diagnostico de NF2 de acuerdo con los criterios de Baser et al e inicio en la infancia. Se realiza una revision bibliografica sobre la evolucion de los criterios diagnosticos en los niños. Conclusiones. El modo de presentacion de la NF2 en la infancia difiere de la presentacion en los adultos. Las manifestaciones iniciales de NF2 en los niños son las alteraciones oculares y cutaneas, no las auditivas. La clinica de inicio mas frecuente en la edad pediatrica es la triada de cataratas subcapsulares posteriores, lesiones intracutaneas en forma de placa o tumores nodulares subcutaneos, y sintomas neurologicos secundarios a la afectacion de pares craneales distintos al VIII par, tronco encefalico o medula espinal. Debido a que los criterios diagnosticos de NF2 son menos sensibles en los pacientes pediatricos, los niños con cataratas congenitas o de aparicion precoz y manifestaciones cutaneas tipicas de NF2 deben ser seguidos estrechamente.

  10. About Neurofibromatosis 1

    MedlinePlus

    ... is very important. Keeping a child in the dark can sometimes create more anxiety. How much you ... themselves should react. Although neurofibromatosis is a serious matter, the calmer you remain, the less anxious the ...

  11. Neurofibromatosis: lymphoscintigraphic observations

    SciTech Connect

    Sty, J.R.; Starshak, R.J.; Woods, G.A.

    1981-06-01

    The authors describe the lymphoscintigraphic findings in a 4-year-old child with neurofibromatosis, the principal manifestation of which was elephantiasis neuromatosa involving the right lower extremity. The lymphoscintigram demonstrated dilated lymphatics and enlarged lymph nodes.

  12. Ophthalmic manifestations of neurofibromatosis.

    PubMed Central

    Huson, S; Jones, D; Beck, L

    1987-01-01

    The eyes of 64 patients known to have neurofibromatosis were examined. Lisch nodules were the commonest manifestation of the disease and were present in 95% of all patients (100% of those aged 16 years or older). Images PMID:3103673

  13. Encefalitis por anticuerpos contra el receptor de NMDA: experiencia con seis pacientes pediátricos. Potencial eficacia del metotrexato

    PubMed Central

    Bravo-Oro, Antonio; Abud-Mendoza, Carlos; Quezada-Corona, Arturo; Dalmau, Josep; Campos-Guevara, Verónica

    2016-01-01

    Introducción La encefalitis por anticuerpos contra el receptor de N-metil-D-aspartato (NMDA) es una entidad cada vez más diagnosticada en edad pediátrica. A diferencia de los adultos, en muchos casos no se asocia a tumores y las manifestaciones iniciales en niños más frecuentes son crisis convulsivas y trastornos del movimiento, mientras que en los adultos predominan las alteraciones psiquiátricas. Casos clínicos Presentamos seis casos pediátricos confirmados con anticuerpos contra la subunidad NR1 del receptor de NMDA en suero y líquido cefalorraquídeo. Cinco de los casos comenzaron con crisis convulsivas como manifestación clínica inicial antes de desarrollar el cuadro clásico de esta entidad. En todos los casos se utilizaron esteroides como primera línea de tratamiento, con los que sólo se observó control de las manifestaciones en uno, por lo que el resto de los pacientes requirió inmunomoduladores de segunda línea. Todos los pacientes recibieron metotrexato como tratamiento inmunomodulador para evitar recaídas y la evolución fue a la mejoría en todos ellos. Conclusiones En nuestra serie de pacientes con encefalitis por anticuerpos contra el receptor de NMDA, ninguno se asoció a tumores. Todos los casos recibieron metotrexato por lo menos durante un año, no observamos eventos adversos clínicos ni por laboratorio, ni hubo secuelas neurológicas ni recaídas durante el tratamiento. Aunque es una serie pequeña y es deseable incrementar el número y tiempo de evolución, consideramos el metotrexato una excelente alternativa como tratamiento inmunomodulador para esta patología. PMID:24150952

  14. Neurofibromatosis type 2

    PubMed Central

    Asthagiri, Ashok R; Parry, Dilys M; Butman, John A; Kim, H Jeffrey; Tsilou, Ekaterini T; Zhuang, Zhengping; Lonser, Russell R

    2016-01-01

    Neurofibromatosis type 2 is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumour suppressor gene located on chromosome 22q. It has a frequency of one in 25 000 livebirths and nearly 100% penetrance by 60 years of age. Half of patients inherit a germline mutation from an affected parent and the remainder acquire a de novo mutation for neurofibromatosis type 2. Patients develop nervous system tumours (schwannomas, meningiomas, ependymomas, astrocytomas, and neurofibromas), peripheral neuropathy, ophthalmological lesions (cataracts, epiretinal membranes, and retinal hamartomas), and cutaneous lesions (skin tumours). Optimum treatment is multidisciplinary because of the complexities associated with management of the multiple, progressive, and protean lesions associated with the disorder. We review the molecular pathogenesis, genetics, clinical findings, and management strategies for neurofibromatosis type 2. PMID:19476995

  15. Genetics Home Reference: neurofibromatosis type 2

    MedlinePlus

    ... Home Health Conditions neurofibromatosis type 2 neurofibromatosis type 2 Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Neurofibromatosis type 2 is a disorder characterized by the growth of ...

  16. Neurofibromatosis (For Parents)

    MedlinePlus

    ... Lessons? Visit KidsHealth in the Classroom What Other Parents Are Reading Your Child's Development (Birth to 3 Years) Feeding Your 1- to 3-Month-Old Feeding Your 4- to 7-Month-Old Feeding Your 8- to 12-Month-Old Feeding Your 1- to 2-Year-Old ... > For Parents > Neurofibromatosis Print A A A What's in this ...

  17. Surgical management of neurofibromatosis.

    PubMed

    Parsons, Colin M; Canter, Robert J; Khatri, Vijay P

    2009-01-01

    Neurofibromatoses are a complex set of genetic diseases with a wide spectrum of clinical manifestations. Life-threatening complications may develop as the result of tumor progression. Surgical intervention is the only effective means of treatment for progressive pain, disfigurement, functional compromise, and malignancy. In the future, molecular advances should allow for the development of targeted therapies to treat patients who have neurofibromatosis in addition to those who have sporadic tumors. Tumor profiling should allow us to guide therapies and predict responses.

  18. Neurofibromatosis and pregnancy. An update.

    PubMed

    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.

  19. [How to recognize neurofibromatosis?].

    PubMed

    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.

  20. Myopia in neurofibromatosis type 1.

    PubMed

    Garty, B Z; Laor, A; Danon, Y L

    1996-05-01

    We studied the prevalence of myopia in 17-year-old Israeli military recruits with neurofibromatosis type 1 (NF1). Twenty-four percent of the youngsters with neurofibromatosis had myopia, compared to 19% of the controls; this difference was statistically significant (P < 0.03). The recruits with NF1 had a slightly lower IQ, fewer years of education, and lower height and weight than the controls. Thus, these factors, which have been reported to be associated with myopia, did not significantly influence the high prevalence of myopia in the neurofibromatosis subjects. A high prevalence of myopia seems to be an additional feature of NF1.

  1. Neurofibromatosis and the Painful Neuroma

    DTIC Science & Technology

    2007-01-01

    tibial nerve exposure group on all postoperative test days except day 33. Thus, proximal tibial nerve transection led to a reversal of the neuroma pain ...AD_________________ Award Number: W81XWH-06-1-0176 TITLE: Neurofibromatosis and the Painful ...TYPE Annual 3. DATES COVERED (From - To) 01 Jan 06 – 31 Dec 06 4. TITLE AND SUBTITLE Neurofibromatosis and the Painful Neuroma 5a. CONTRACT

  2. Gene Therapy for Childhood Neurofibromatosis

    DTIC Science & Technology

    2014-05-01

    AD_________________ Award Number: W81XWH-13-1-0101 TITLE: Gene Therapy for Childhood ...May 2014 4. TITLE AND SUBTITLE Gene Therapy for Childhood Neurofibromatosis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0101 5c...technology. This approach still represents a plausible and very different way to treat childhood neurofibromatosis, as well as other solid tumors

  3. Autoimmune diseases associated with neurofibromatosis type 1.

    PubMed

    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.

  4. Neurofibromatosis type 1

    PubMed Central

    Boyd, Kevin P.; Korf, Bruce R.; Theos, Amy

    2009-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder affecting approximately 1 in 3500 people. Significant advances in the understanding of the pathophysiology of NF1 have been made in the last decade. While no medical therapies are currently available, trials are ongoing to discover and test medical treatments for the various manifestations of NF1, primarily plexiform neurofibromas, learning disabilities, and optic pathway gliomas. Additionally, mutational analysis has become available on a clinical basis and is useful for diagnostic confirmation in individuals who do not fulfill diagnostic criteria or when prenatal diagnosis is desired. There are several disorders which may share overlapping features with NF1; in 2007, a disorder with cutaneous findings similar to NF1 was described. This paper addresses the dermatologist's role in diagnosis and management of NF1 and describes the variety of cutaneous and extracutaneous findings in NF1 to which the dermatologist may be exposed. PMID:19539839

  5. Scoliosis associated with neurofibromatosis.

    PubMed

    Crawford, Alvin H; Herrera-Soto, Jose

    2007-10-01

    Neurofibromatosis type 1 (NF-1) is a multisystemic disease. It may manifest as abnormalities of the nervous tissue, bones, soft tissue, and skin. The manifestations of NF-1 vary from person to person and range from subclinical to severe. Individuals who carry the gene eventually exhibit some clinical feature of the disease. The penetrance for NF-1 nears 100% during adulthood. Skeletal abnormalities are common in NF-1, with most patients presenting with some type of bony dysplasia. The orthopedic complications usually appear early. They include spinal deformities, such as scoliosis or kyphosis, congenital tibial dysplasia with bowing and pseudarthrosis of the tibia, forearm, other bones, as well as overgrowth phenomenon of an extremity, and soft tissue tumors.

  6. Perioperative Management of Neurofibromatosis Type 1

    PubMed Central

    Fox, Charles J.; Tomajian, Samir; Kaye, Aaron J.; Russo, Stephanie; Abadie, Jacqueline Volpi; Kaye, Alan D.

    2012-01-01

    Neurofibromatosis type 1 (neurofibromatosis-1), a relatively common single-gene disorder, is caused by a mutation of the NF1 gene that results in a loss of activity or in a nonfunctional neurofibromin protein. Clinical anesthesiologists may find patients with neurofibromatosis-1 challenging because this condition may affect most organ systems and result in a wide variety of presentations and clinical implications. Current neurofibromatosis-1 research studies include genotype-phenotype correlations, investigation of the pathoetiology behind the different clinical manifestations of neurofibromatosis-1, and the search for treatment options for the different features of the disorder. Neurofibromatosis-1–associated complications of the central nervous, respiratory, cardiovascular, musculoskeletal, and gastrointestinal and genitourinary systems all present various degrees of considerations for anesthesiologists. Additionally, neurofibromatosis-1 has dramatic implications for pregnant women. PMID:22778675

  7. Neurofibromatosis in children.

    PubMed

    Crawford, A H

    1986-01-01

    The clinical diagnosis of neurofibromatosis in childhood will usually be based on the presence of numerous café-au-lait spots. Early diagnosis allows for continuing follow-up and appropriate counselling. Symptomatic therapy can be provided if necessary. The disorder has a tendency via its mesodermal route to affect almost every system in the body; however, few laymen have even heard of the disorder and, except for the "Elephant Man" notoriety, are totally unaware of it, whereas muscular dystrophy, cystic fibrosis, and Down syndrome although occurring less frequently are well known to the general public. The management of neurofibromatosis in children covers an extremely wide spectrum: at times the management appears to be simple, involving little more than clinical evaluation and simple investigations. However, in view of the protean manifestations of the condition, a complete history including family history is obligatory, and investigation must include radiographic studies of the abdomen, chest, spine, and skull, the latter to include special views of the orbits and optic foramina. My investigation of this disorder has been extremely frustrating because of the progressive character of the disease. Nothing seems to alter the natural course of the disease. I cannot say that my investigative efforts have revealed any breakthroughs in treatment. An aggressive surgical approach to the myriad of lesions associated with this disease, especially neuromata or segmental problems, is probably advisable. The early treatment of tibial pseudarthrosis by polyprophylene orthotic and pulsating electromagnetic fields shows encouraging results over the short course, although I am not so sure as to whether or not the patients would do as well with the custom fit orthotic with or without the electronics. Early stabilization of spinal deformity has proven to be more than moderately successful and is strongly recommended following appropriate intraspinal evaluation. The management of

  8. Segmental neurofibromatosis with deep schwannoma

    PubMed Central

    Smith, Wallace A.; Buhalog, Brittany A.; Fiala, Katherine H.

    2016-01-01

    An elderly patient presented with two clusters of asymptomatic fleshy and pedunculated papules. Biopsy of the papules was consistent with neurofibromas. Decades prior she had undergone a surgery for the excision of a large schwannoma. Given her lack of other neurofibromatosis findings, the patient was diagnosed with multisegmental neurofibromatosis (multi-SN) with deep schwannoma, a possible new phenotype of SN. Because this entity may be associated with internal malignancy, it is important to screen and educate these patients as well as to provide regular follow-up. PMID:27990385

  9. Segmental neurofibromatosis: report of 3 cases.

    PubMed

    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.

  10. Neurofibromatosis: part 2--clinical management.

    PubMed

    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.

  11. Hearing Restoration in Neurofibromatosis Type II Patients

    PubMed Central

    Lee, Jeon Mi; Chang, Jin Woo; Choi, Jae Young

    2016-01-01

    Patients with neurofibromatosis type II will eventually succumb to bilateral deafness. For patients with hearing loss, modern medical science technology can provide efficient hearing restoration through a number of various methods. In this article, several hearing restoration methods for patients with neurofibromatosis type II are introduced. PMID:27189272

  12. Preclinical Mouse Models of Neurofibromatosis

    DTIC Science & Technology

    2005-11-01

    Tumor Center, Henry Ford Hospital, Detroit, MI 48202, USA; 5Department of Biology and Center for Cancer Research, and Howard Hughes Medical Institute...206. Lomas, J., Bello, M.J., Arjona, D., Alonso, M.E., Martinez-Glez, V., Lopez-Marin, I., Aminoso, C., de Campos , J.M., Isla, A., Vaquero, J., et al... Varga , M., Ramesh, V., Gusella, J., and Maruta, H. 1994. An anti-Ras function of neurofibromatosis type 2 gene product (NF2/Merlin). J. Biol. Chem

  13. Clinical variability of type 1 neurofibromatosis: is there a neurofibromatosis-Noonan syndrome?

    PubMed Central

    Stern, H J; Saal, H M; Lee, J S; Fain, P R; Goldgar, D E; Rosenbaum, K N; Barker, D F

    1992-01-01

    Detailed clinical, ophthalmological, and molecular studies were performed on a multigeneration family in which there were many subjects with type 1 neurofibromatosis, a common autosomal dominant disorder. Affected family members displayed a wide range of clinical findings including, in two subjects, features seen in Noonan syndrome (triangular facies, downward slanting palpebral fissures, micrognathia, short stature, and learning disability). Subjects have been described previously whose features have overlapped with neurofibromatosis and Noonan syndrome, and it has been suggested that these persons might represent a separate condition. DNA haplotype analysis showed linkage of the neurofibromatosis phenotype seen in this family to the proximal long arm of chromosome 17 in the region where the type 1 neurofibromatosis gene has been mapped. These results imply that the Noonan phenotype seen in some patients with type 1 neurofibromatosis might be the result of variable or variant expression of the neurofibromatosis gene on chromosome 17. The possible role of non-specific factors, such as fetal hypotonia, in producing the neurofibromatosis-Noonan phenotype needs further investigation. The availability of closely linked and intragenic molecular markers for neurofibromatosis could potentially be useful in the diagnosis and characterisation of patients and families with atypical forms of neurofibromatosis. Images PMID:1348094

  14. Computed tomography of orbital-facial neurofibromatosis

    SciTech Connect

    Zimmerman, R.A.; Bilaniuk, L.T.; Metzger, R.A.; Grossman, R.I.; Schut, L.; Bruce, D.A.

    1983-01-01

    Twenty-four patients with orbital-facial manifestations of neurofibromations were examined by computed tomography. Delineation of the extent of the disease, and differentiation of the disease processes (orbital tumor, osseous orbital dysplasia, plexiform neurofibromatosis, and buphthalmos) was possible.

  15. [Genetics of neurofibromatosis: recent progress and prospects].

    PubMed

    Maillet-Vioud, M; Narod, S; Assouline, D; Sobol, H; Fischer, G; Robert, J M; Lenoir, G M

    1991-01-01

    Two forms of neurofibromatosis are currently described. Von Reckinghausen Neurofibromatosis (NF 1) is the classic and common form, recently localised to chromosome 17. Neurofibromatosis type 2 (NF 2) or bilateral acoustic Neurofibromatosis, formerly the "central form" of von Reckinghausen disease, is characterized by multiple brain tumors, most often bilateral acoustic neuromas. The NF 2 mutation lies on the long arm of chromosome 22. The two forms predispose to benign or malignant familial tumors, derived from neural crest germ lines, such as Schwann cells. Rapid progress in the understanding of mechanisms underlying neurological tumor formation is expected in these inherited diseases. Molecular biology will allow the precise identification of genes responsible for the neurofibromatose syndromes. Practical applications, such as screening of individuals at risk for the disease will soon be available. Medical follow-up and genetic counselling should improve as a result of these advances.

  16. A rare case of segmental neurofibromatosis involving the sciatic nerve.

    PubMed

    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.

  17. The "elephant man" of Cambridge. a case report of neurofibromatosis.

    PubMed

    Rai, G S; Coni, N K

    1981-03-01

    The case is presented of a 65-year-old man with neurofibromatosis manifesting facial and skeletal features resembling those of the "elephant man" described by Sir Frederick Treves. Autopsy revealed not only a pheochromocytoma (a common accompaniment of neurofibromatosis), but an enlarged infarcted spleen and a subphrenic abscess. These findings have not been described previously in a patient with neurofibromatosis.

  18. Segmental neurofibromatosis: a rare variant of a common genodermatosis.

    PubMed

    Morais, P; Ferreira, O; Bettencourt, H; Azevedo, F

    2010-10-01

    Segmental neurofibromatosis is a rare disorder characterized by features of neurofibromatosis type 1 circumscribed to a particular body segment. This entity is considered to be the result of a somatic mosaicism and is still under-diagnosed. We report a case of segmental neurofibromatosis and give a brief and up-to-date overview of the disease.

  19. Neurofibromatosis

    MedlinePlus

    ... connects the eye to the brain is the optic nerve. The optic nerve can develop a benign tumor called a ... required. Unfortunately, the eyelid lesion may recur. Frequently, optic nerve gliomas simply require observation by serial examinations ...

  20. Neurofibromatosis

    MedlinePlus

    ... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Information Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ...

  1. Neurofibromatosis

    MedlinePlus

    ... genes. Once this change has taken place, the mutant gene can be passed on to succeeding generations. ... genes. Once this change has taken place, the mutant gene can be passed on to succeeding generations. ...

  2. Posttranscriptional Regulation of the Neurofibromatosis 2 Gene

    DTIC Science & Technology

    2005-08-01

    14 . ABSTRACT Neurofibromatosis type 2 (NF2) is associated with a homozygous inactivation of the neurofibromatosis 2 (NF2) gene. Despite intense...direct β-galactosidase (β-gal) reporter expression as early as embryonic day 5.5 (E5.5). NF2 promoter activity was first detected in the embryonic...8 carrying a 2.4-kb NF2 promoter-driven the lacZ gene with a nuclear localization signal. Whole- mount X-gal staining of embryos at various days

  3. Evidence of chromosomal instability in neurofibromatosis

    SciTech Connect

    Hafez, M.; Sharaf, L.; Abd el-Nabi, S.M.; el-Wehedy, G.

    1985-05-15

    Blood lymphocytes from six unrelated patients with neurofibromatosis and three normal controls were examined for their response to different doses (0, 75, 150, 300, 400 rad) of x-radiation, as measured by chromosome aberrations (gaps, breaks, dicentrics, centric rings, acentric ring, fragments, and minutes). Cytogenetic studies on phytohemagglutinin-stimulated cells revealed chromosomal instability in the neurofibromatosis lymphocytes as shown by the significant increase in the in the incidence of gaps, breaks and dicentrics. This increase paralleled the increase in the dose of irradiation. The significance of these findings is discussed.

  4. Brain tumors in children with neurofibromatosis: additional neuropsychological morbidity?

    PubMed Central

    De Winter, A. E.; Moore, B. D.; Slopis, J. M.; Ater, J. L.; Copeland, D. R.

    1999-01-01

    Neurofibromatosis type 1 is a common autosomal dominant genetic disorder associated with numerous physical anomalies and an increased incidence of neuropsychological impairment. Tumors of the CNS occur in approximately 15% of children with neurofibromatosis, presenting additional risk for cognitive impairment. This study examines the impact of an additional diagnosis of brain tumor on the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological tests was administered to 149 children with neurofibromatosis. Thirty-six of these children had a codiagnosis of brain tumor. A subset of 36 children with neurofibromatosis alone was matched with the group of children diagnosed with neurofibromatosis and brain tumor. Although mean scores of the neurofibromatosis plus brain tumor group were, in general, lower than those of the neurofibromatosis alone group, these differences were not statistically significant. Children in the neurofibromatosis plus brain tumor group who received cranial irradiation (n = 9) demonstrated weaker academic abilities than did children with brain tumor who had not received that treatment. These results suggest that neurofibromatosis is associated with impairments in cognitive functioning, but the severity of the problems is not significantly exacerbated by the codiagnosis of a brain tumor unless treatment includes cranial irradiation. PMID:11550319

  5. Genetics Home Reference: neurofibromatosis type 1

    MedlinePlus

    ... of neurofibromatosis type 1. Semin Pediatr Neurol. 2006 Mar;13(1):8-20. Review. Citation on PubMed ... PubMed Rose VM. Neurocutaneous syndromes. Mo Med. 2004 Mar-Apr;101(2):112-6. Review. Citation on ...

  6. Craniofacial neurofibromatosis: treatment of the midface deformity.

    PubMed

    Singhal, Dhruv; Chen, Yi-Chieh; Tsai, Yueh-Ju; Yu, Chung-Chih; Chen, Hung Chang; Chen, Yu-Ray; Chen, Philip Kuo-Ting

    2014-07-01

    Craniofacial Neurofibromatosis is a benign but devastating disease. While the most common location of facial involvement is the orbito-temporal region, patients often present with significant mid-face deformities. We reviewed our experience with Craniofacial Neurofibromatosis from June 1981 to June 2011 and included patients with midface soft tissue deformities defined as gross alteration of nasal or upper lip symmetry. Data reviewed included the medical records and photobank. Over 30 years, 52 patients presented to and underwent surgical management for Craniofacial Neurofibromatosis at the Chang Gung Craniofacial Center. 23 patients (43%) demonstrated gross mid-facial deformities at initial evaluation. 55% of patients with lip deformities and 28% of patients with nasal deformities demonstrated no direct tumour involvement. The respective deformity was solely due to secondary gravitational effects from neurofibromas of the cheek subunit. Primary tumour infiltration of the nasal and/or labial subunits was treated with excision followed by various methods of reconstruction including lower lateral cartilage repositioning, forehead flaps, free flaps, and/or oral commissure suspension. Soft tissue deformities of the midface are very common in patients with Craniofacial Neurofibromatosis and profoundly affect overall aesthetic outcomes. Distinguishing primary from secondary involvement of the midface assists in surgical decision making.

  7. Learning Disability Subtypes in Children with Neurofibromatosis.

    ERIC Educational Resources Information Center

    Brewer, Vickie R.; Moore, Bartlett D., III; Hiscock, Merrill

    1997-01-01

    This study investigated the incidence of learning disabilities in 105 children (ages 6-18) with neurofibromatosis Type 1 (NF-1). Results found that nearly 70% of the subjects were academically deficient and 42% met the criteria for learning disabilities. A low incidence of visuospatial-constructional deficits was also found. (Author/CR)

  8. Neurofibromatosis with unilateral lower limb gigantism.

    PubMed

    Sabbioni, Giacomo; Rani, Nicola; Devescovi, Valentina

    2010-05-01

    The case of a 3-year-old child diagnosed with Type 1 neurofibromatosis is presented, showing pigmented birthmarks and gigantism of the left lower limb associated with the presence of multiple neurofibromas. Increased bone growth appears to be the direct or indirect consequence of a still undefined paracrine effect of nerve tumor cells.

  9. Neurofibromatosis type II presenting as vertical diplopia.

    PubMed

    Sokwala, Ahmed; Knapp, Christopher; Gottlob, Irene

    2004-09-01

    Neurofibromatosis type II (NF II) is rare and most commonly presents with hearing loss, tinnitus and/or vestibular disturbance in the third decade of life. The authors describe a rare case presenting with NF II with vertical diplopia due to IV(th) nerve palsy. The patient was otherwise asymptomatic despite multiple extensive lesions on MRI.

  10. Neurofibromatosis-Noonan syndrome: case report and clinicopathogenic review of the Neurofibromatosis-Noonan syndrome and RAS-MAPK pathway.

    PubMed

    Reig, Irela; Boixeda, Pablo; Fleta, Beatriz; Morenoc, Carmen; Gámez, Lucía; Truchuelo, Mayte

    2011-04-15

    Neurofibromatosis-Noonan syndrome is an entity that combines both features of Noonan syndrome and Neurofibromatosis type 1. This phenotypic overlap can be explained by the involvement of the RAS-MAPK pathway (mitogen-activated protein kinase) in both disorders. We report the case of a 17-year-old boy with Neurofibromatosis 1 with Noonan-like features, who complained of the progressive appearance of blue-gray lesions on his back.

  11. Neurofibromatosis: chronological history and current issues.

    PubMed

    Antônio, João Roberto; Goloni-Bertollo, Eny Maria; Trídico, Lívia Arroyo

    2013-01-01

    Neurofibromatosis, which was first described in 1882 by Von Recklinghausen, is a genetic disease characterized by a neuroectodermal abnormality and by clinical manifestations of systemic and progressive involvement which mainly affect the skin, nervous system, bones, eyes and possibly other organs. The disease may manifest in several ways and it can vary from individual to individual. Given the wealth of information about neurofibromatosis, we attempted to present this information in different ways. In the first part of this work, we present a chronological history, which describes the evolution of the disease since the early publications about the disorder until the conclusion of this work, focusing on relevant aspects which can be used by those wishing to investigate this disease. In the second part, we present an update on the various aspects that constitute this disease.

  12. [Management of craniofacial type 1 neurofibromatosis].

    PubMed

    Bachelet, J T; Combemale, P; Devic, C; Foray, N; Jouanneau, E; Breton, P

    2015-09-01

    Type I neurofibromatosis (NF) is the most common autosomal dominant disease. It concerns one in 3000 births, the penetrance is close to 100% and 50% of new cases are de novo mutations (17q11.2 chromosome 17 location). Cranio-maxillofacial region is concerned in 10% of the cases, in different forms: molluscum neurofibroma, plexiform neurofibroma, cranio-orbital neurofibroma, parotido-jugal neurofibroma, cervical neurofibroma. These lesions have different prognosis depending on the craniofacial localization: ocular functional risk, upper airway compressive risk, nerve compression risk, aesthetic and social impact. The maxillofacial surgeon in charge of patients with type I NF should follow the patient from the diagnosis and organize the different surgical times in order to take care about the different issues: vital, functional and aesthetic. We describe the treatment of facial localizations of type 1 NF as it is done at the University Hospital of Lyon and at the Rhône-Alpes-Auvergne neurofibromatosis reference center.

  13. Neurofibromatosis: chronological history and current issues*

    PubMed Central

    Antônio, João Roberto; Goloni-Bertollo, Eny Maria; Trídico, Lívia Arroyo

    2013-01-01

    Neurofibromatosis, which was first described in 1882 by Von Recklinghausen, is a genetic disease characterized by a neuroectodermal abnormality and by clinical manifestations of systemic and progressive involvement which mainly affect the skin, nervous system, bones, eyes and possibly other organs. The disease may manifest in several ways and it can vary from individual to individual. Given the wealth of information about neurofibromatosis, we attempted to present this information in different ways. In the first part of this work, we present a chronological history, which describes the evolution of the disease since the early publications about the disorder until the conclusion of this work, focusing on relevant aspects which can be used by those wishing to investigate this disease. In the second part, we present an update on the various aspects that constitute this disease. PMID:23793209

  14. Studies of Neurofibromatosis-1 Modifier Genes

    DTIC Science & Technology

    2005-06-01

    DATE (DD-MM-YYYY) 2 . REPORT TYPE 3. DATES COVERED (From - To) 01-06-2005 Annual 1 Jun 2004 - 31 May 2005 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER...will test whether neurofibroma numerical variability reflects (1) allelic differences in genes that maintain genome stability; ( 2 ) differences in the NF1...12 Introduction Neurofibromatosis type 1 (NF1) affects approximately 2 -3 in 10,000 worldwide. A high degree of

  15. Lethal presentation of neurofibromatosis and Noonan syndrome.

    PubMed

    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.

  16. A Neuropsychological Perspective on Attention Problems in Neurofibromatosis Type 1

    ERIC Educational Resources Information Center

    Templer, Alexandra K.; Titus, Jeffrey B.; Gutmann, David H.

    2013-01-01

    Cognitive problems are common in children with neurofibromatosis type 1 and they can often complicate treatment. The current literature review examines cognitive functioning in neurofibromatosis type 1, with a specific focus on executive functioning. This includes exploration of how deficits in executive functioning are expressed in children with…

  17. Moyamoya syndrome and neurofibromatosis type 1

    PubMed Central

    2014-01-01

    Neurofibromatosis type 1 (NF1) is the most prevalent autosomal dominant genetic disorder among humans. NF1 vasculopathy is a significant but underrecognized complication of the disease, affecting both arterial and venous blood vessels of all sizes. Moyamoya syndrome is a cerebral vasculopathy that is only rarely observed in association with NF1, particularly in the pediatric age range. Herein, we report of a 5-year-old female with NF1 and moyamoya syndrome and we briefly review the existing literature. PMID:24952383

  18. CT of sarcomatous degeneration in neurofibromatosis

    SciTech Connect

    Coleman, B.G.; Arger, P.H.; Dalinka, M.K.; Obringer, A.C.; Raney, B.R.; Meadows, A.T.

    1983-02-01

    Neurofibromatosis is a relatively common disorder that often involves many organ systems. One of the least understood aspects of this malady is a well documented potential for sarcomatous degeneration of neurofibromas. The inability to identify patients at risk and the lack of noninvasive screening methods for symptomatic patients often leads to late diagnosis. In six of seven subsequently proven neurofibrosarcomas, CT demonstrated low-density areas that histopathologically appeared to be due to necrosis, hemorrhage, and/or cystic degeneration. The density differences within these sarcomas were enhanced by the intravenous adminstration of iodinated contrast agents.

  19. Cognitive profile of neurofibromatosis type 1.

    PubMed

    Levine, Terry M; Materek, April; Abel, Jessica; O'Donnell, Madeline; Cutting, Laurie E

    2006-03-01

    General consensus has yet to be reached with regard to the exact cognitive profile of children with neurofibromatosis type 1 (NF1). The current overview seeks to provide a more comprehensive review of the literature by examining studies that have specifically compared individuals with NF1 to siblings, controls, and/or norms. We also examined results of studies that compared individuals with NF1 with various manifestations to each other. Consistent with previous reviews, no clear cognitive profile emerged; however, greater insight into patterns was obtained. Additionally, future directions for research on NF1 were suggested.

  20. Coincidence of neurofibromatosis and myotonic dystrophy in a kindred.

    PubMed Central

    Ichikawa, K; Crosley, C J; Culebras, A; Weitkamp, L

    1981-01-01

    Neurofibromatosis and myotonic dystrophy have occurred in ten members of a nonconsanguineous family with a high degree of concordance. The expression of neurofibromatosis is peripheral, and the expression of myotonic dystrophy has produced at least moderately severe disability. Neither disease has appeared to alter the phenotypic expression of the other when both have occurred simultaneously. Secretor typing supports the assumption that the myotonic dystrophy in this family is the commonly recognised secretor-linked entity. The segregation pattern of the two disorders in this family suggest the possibility of close linkage between the loci for neurofibromatosis and myotonic dystrophy. PMID:6787200

  1. Ullrich-Turner syndrome and neurofibromatosis-1

    SciTech Connect

    Schorry, E.K.; Lovell, A.M.; Saal, H.M.; Milatovich, A.

    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.

  2. Metaplastic Breast Cancer in a Patient with Neurofibromatosis

    PubMed Central

    Chaudhry, Umar Shafique; Yang, Limin; Askeland, Ryan W; Fajardo, Laurie L

    2015-01-01

    Metaplastic breast cancer is a rare malignancy in the breast. Neurofibromatosis Type 1 is an autosomal dominant multisystem disorder associated with multiple neoplasms such as optic gliomas and peripheral nerve sheath tumors. The association of breast cancer with neurofibromatosis is very rare. We present a case of a metaplastic breast cancer in a patient with Type 1 neurofibromatosis. The patient presented with a palpable mass in her left breast with suspicious findings on mammogram and ultrasound. Ultrasound-guided percutaneous biopsy showed metaplastic breast carcinoma with metastasis to an axillary lymph node. This is the third case report in the English literature to show metaplastic breast carcinoma in a patient with Type 1 neurofibromatosis. In this report we review recent literature and discuss the association between these two entities. PMID:25883857

  3. Metaplastic breast cancer in a patient with neurofibromatosis.

    PubMed

    Chaudhry, Umar Shafique; Yang, Limin; Askeland, Ryan W; Fajardo, Laurie L

    2015-01-01

    Metaplastic breast cancer is a rare malignancy in the breast. Neurofibromatosis Type 1 is an autosomal dominant multisystem disorder associated with multiple neoplasms such as optic gliomas and peripheral nerve sheath tumors. The association of breast cancer with neurofibromatosis is very rare. We present a case of a metaplastic breast cancer in a patient with Type 1 neurofibromatosis. The patient presented with a palpable mass in her left breast with suspicious findings on mammogram and ultrasound. Ultrasound-guided percutaneous biopsy showed metaplastic breast carcinoma with metastasis to an axillary lymph node. This is the third case report in the English literature to show metaplastic breast carcinoma in a patient with Type 1 neurofibromatosis. In this report we review recent literature and discuss the association between these two entities.

  4. Prevalence of Sleep Disturbances in Children with Neurofibromatosis Type 1

    PubMed Central

    Licis, Amy K.; Vallorani, Alicia; Gao, Feng; Chen, Cynthia; Lenox, Jason; Yamada, Kelvin A.; Duntley, Stephen P.; Gutmann, David H.

    2013-01-01

    Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder, neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2-17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. While the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a co-existing attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population. PMID:24065580

  5. A case of late-onset segmental neurofibromatosis.

    PubMed

    McLimore, Heather; McCaughey, Cort; Vanness, Erin

    2014-04-01

    Segmental neurofibromatosis (NF5) is a rare variant of neurofibromatosis. To our knowledge, there have been few reports of cases presenting later in life. The recognition of NF5 is important, as there have been reports of paraneoplastic manifestations and transmission to offspring. Here we present the case of a patient who presented with NF5 first appearing in her mid-50s. This case illustrates the subtle nature of NF5, which often leads to misdiagnosis.

  6. Von Hippel's disease in association with von Recklinghausen's neurofibromatosis.

    PubMed Central

    Thomas, J V; Schwartz, P L; Gragoudas, E S

    1978-01-01

    Ten members of a large family who showed manifestations of either von Hippel-Lindau disease or von Recklinghausen's neurofibromatosis were examined. Three of 10 members were found to have retinal angiomas which had not been present on fundus examination 3 years previously. These angiomas were associated with ocular and systemic signs of neurofibromatosis. These cases show overlapping manifestations of different phakomatoses and provide support for the concept of a common aetiology for these diseases. Images PMID:101230

  7. Myocardial infarction in a 17-year-old patient due to neurofibromatosis-associated coronary aneurysm.

    PubMed

    Evrengul, Harun; Kilic, Dogu I; Zungur, Mustafa; Alihanoglu, Yusuf I; Tanriverdi, Halil

    2013-06-01

    Neurofibromatosis is an autosomal dominant multi-system genetic disorder. Extra-cardiac vascular manifestations of neurofibromatosis have been previously described in many reports. However, coronary arterial involvements have been rarely described. A 17-year-old girl with neurofibromatosis presented to our institute with subacute myocardial infarction. Coronary angiogram revealed an aneurysm with thrombus in the left anterior descending artery.

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

    PubMed

    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".

  9. Spontaneous Hemothorax in Neurofibromatosis Treated with Percutaneous Embolization

    SciTech Connect

    Arai, Kazunori; Sanada, Junichiro Kurozumi, Akiko; Watanabe, Toshio; Matsui, Osamu

    2007-06-15

    We evaluated the effectiveness of transcatheter arterial coil embolization therapy for the treatment of spontaneous hemothorax followed by aneurysm rupture in neurofibromatosis patients. Three patients were treated for massive hemothorax caused by arterial lesions associated with neurofibromatosis. Bleeding episodes were secondary to ascending cervical artery aneurysm and dissection of vertebral artery in 1 patient, and intercostal artery aneurysm with or without arteriovenous fistula in 2 patients. Patients were treated by transarterial coil embolization combined with chest drainage. In 1 patient, the ruptured ascending cervical artery aneurysm was well embolized but, shortly after the embolization, fatal hemorrhage induced by dissection of the vertebral artery occurred and the patient died. In the other 2 patients, the ruptured intercostal artery aneurysm was well embolized and they were successfully treated and discharged. Transcatheter arterial coil embolization therapy is an effective method for the treatment of spontaneous hemothorax followed by aneurysm rupture in neurofibromatosis patients.

  10. Neurofibromatosis, stroke and basilar impression. Case report.

    PubMed

    Piovesan, E J; Scola, R H; Werneck, L C; Zétola, V H; Nóvak, E M; Iwamoto, F M; Piovesan, L M

    1999-06-01

    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.

  11. Mutational analysis of patients with neurofibromatosis 2

    SciTech Connect

    MacCollin, M.; Ramesh, V.; Pulaski, K.; Trofatter, J.A.; Short, M.P.; Bove, C.; Jacoby, L.B.; Louis, D.N.; Rubio, M.P.; Eldridge, R.

    1994-08-01

    Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member, merlin, of the protein 4.1 family of cytoskeleton-associated proteins. To define the molecular basis of NF2 in affected individuals, the authors have used SSCP analysis to scan the exons of the NF2 gene from 33 unrelated patients with NF2. Twenty unique SSCP variants were seen in 21 patients; 10 of these individuals were known to be the only affected person in their kindred, while 7 had at least one other known affected relative. In all cases in which family members were available, the SSCP variant segregated with the disease; comparison of sporadic cases with their parents confirmed the de novo variants. DNA sequence analysis revealed that 19 of the 20 variants observed are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. A single patient carried a 3-bp deletion removing a phenylalanine residue. The authors conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare. 18 refs., 3 figs., 2 tabs.

  12. Neurofibromatosis type 2 service delivery in England.

    PubMed

    Lloyd, S K; Evans, D G

    2016-01-27

    Neurofibromatosis type 2 (NF2) is a complex disease characterized by the development of multiple schwannomas, especially vestibular schwannomas, as well as other types of benign tumours including meningioma and spinal ependymoma. Due to its multisystem nature, the management of NF2 requires a multidisciplinary approach. In England, the delivery of care for NF2 patients has been centralized to four-"hub" centres in Manchester, Cambridge, Oxford and London each having associated "spoke" centres. Each centre has a core multidisciplinary team consisting of genetics, otolaryngology, neurosurgery, paediatrics, neurology, audiology, radiology, psychology, physiotherapy, specialist nurses and administrative staff. In addition, the core team has access to plastic surgery, ophthalmology, peripheral nerve surgery and adult and paediatric oncology. There are weekly multidisciplinary clinics each with six to eight patients. Each patient is discussed during a team meeting and the management decisions that are made are then discussed with the patients. All patients are reviewed at least annually and have annual head magnetic resonance imaging (MRI) and three yearly spinal MRI. Annual audiological assessment is performed. Cochlear implantation and auditory brainstem implantation are offered if indicated. Surgery, stereotactic radiosurgery and bevacizumab therapy are available for the management of intracranial and spinal tumours. The integration of the service in England has provided significant benefits to patient care and, in the long term, will provide robust patient outcome data that will provide an evidence base to assist in optimizing management of patients with NF2.

  13. Orthopaedic manifestations of neurofibromatosis type 1.

    PubMed

    Feldman, David S; Jordan, Charles; Fonseca, Lauren

    2010-06-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominant disease that affects 1 in 3,000 persons worldwide. Café-au-lait macules and peripheral nerve sheath tumors (ie, neurofibromas) are the most commonly recognized manifestations of NF-1. However, NF-1 affects multiple organ systems, and a multidisciplinary approach to treatment is required. Management of the orthopaedic manifestations of NF-1 is often difficult. The most complex manifestations are scoliosis (dystrophic and nondystrophic), congenital pseudarthrosis of the tibia, and problems related to soft-tissue tumors. Metabolic bone disease is common; many patients are frankly osteopenic, which further complicates treatment. Dystrophic scoliosis, which may be caused by either bony dysplasia or intraspinal pathology, is characterized by early presentation and rapid progression. Pseudarthrosis is common even after instrumented fusion. Nondystrophic scoliosis tends to behave like adolescent idiopathic scoliosis, although it may present earlier and is associated with a higher rate of pseudarthrosis. Congenital pseudarthrosis of the tibia is a long-bone dysplasia that afflicts patients with NF-1. Management of this osseous deformity is challenging. Failure to achieve union and refracture are common.

  14. Equatorial Staphyloma Associated with Neurofibromatosis Type 1

    PubMed Central

    Shimada, Yoshiaki; Horiguchi, Masayuki

    2016-01-01

    We report a case of a 38-year-old man who presented with a recently self-detected lump under his left eyebrow. Previous ophthalmological history was unremarkable except for unilateral high myopia (left eye) since childhood. The appearance of the left eye was seemingly normal; however, with the top lid pulled up on downward gaze, a dark brown bulge emerged. The bulge was 10 × 7 mm and approximately 4 mm in height, and was covered by the extended superior rectus muscle. The diagnosis of equatorial staphyloma was made after coronal T1-weighted magnetic resonance imaging of the orbit revealed the dilatation of the vitreous cavity. Ocular movements were fully maintained and visual acuity was largely spared: 20/15 in the right eye without correction and 20/25 in the left eye with −10.00 spheres and −4.00 × 80 degrees cylinders. His past and family histories were unremarkable; however, small neurofibromas and café au lait spots all over his body led to the diagnosis of neurofibromatosis type 1 (NF1). From this case, similar to previous reports, we suggest that manifestations of NF1 are extremely variable and unpredictable. PMID:27721788

  15. Neurofibromatosis type 1 with overlap Turner syndrome and Klinefelter syndrome.

    PubMed

    Hatipoglu, Nihal; Kurtoglu, Selim; Kendirci, Mustafa; Keskin, Mehmet; Per, Hüseyin

    2010-02-01

    Turner's syndrome is a sex chromosome disorder. Klinefelter's syndrome is one of the most severe genetic diseases. Neurofibromatosis is an autosomal dominant disorder characterized by cafe-au-lait spots and fibromatous tumors of the skin. In this article, we report the overlap of neurofibromatosis-1 with Turner and Klinefelter syndromes. Thus, these disorders might overlap within the same patient. Due to these cases, we suggest that each patient with Turner-like symptoms or Klinefelter's-like syndrome, be carefully examined for café au lait macules before the initiation of hormone replacement treatment.

  16. Renal vascular disease in neurofibromatosis type 2: association or coincidence?

    PubMed

    Cordeiro, Nuno J V; Gardner, Kate R; Huson, Susan M; Stewart, Helen; Elston, John S; Howard, Emma L; Tullus, Kjell O; Pike, Michael G

    2006-01-01

    Neurofibromatosis type 2 (NF2) remains a challenging diagnosis in childhood where there may be no neurological involvement. A 12-month-old male in whom NF2 was suspected because of characteristic ophthalmological and cutaneous lesions is reported. Cranial MRI showed no tumours. A pathogenic mutation was identified on NF2 gene analysis. The child developed hypertension due to renal vascular disease. Although renal vascular disease is a recognized complication of neurofibromatosis type 1 (NF1), it has not been reported in NF2.

  17. The endovascular management of a neurofibromatosis vasculopathy: a case report.

    PubMed

    Choong, Andrew; Alagaratnam, Swethan; Suliman, Samir; Gikas, Panagiotis; Briggs, Timothy; Loh, Alexander; Lotzof, Kevin

    2012-10-01

    We describe the management of a 30-year-old male with type I neurofibromatosis who required an above-knee amputation for bleeding, infection, swelling, and multiple severe joint instability. Postoperatively, he continued to bleed from the stump site. Angiography revealed multiple small distal bleeding aneurysms. Hemostasis was eventually achieved with standard microcoil embolization.

  18. Autism Spectrum Disorder Profile in Neurofibromatosis Type I

    ERIC Educational Resources Information Center

    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…

  19. Neurogenic tumors of the duodenum in patients with neurofibromatosis

    SciTech Connect

    Tishler, J.M.; Han, S.Y.; Colcher, H.; Halpern, N.B.

    1983-10-01

    Neurogenic tumors of the duodenum may occur in patients with neurofibromatosis. They may be solitary or multiple and are located distal to the duodenal bulb. The presenting complaints may be hematemesis, vomiting, or jaundice. The lesions are generally benign and have a low potential for malignant degenertion. Four cases are reported.

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

    ERIC Educational Resources Information Center

    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…

  1. Generalized metabolic bone disease in Neurofibromatosis type I

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  2. Early Grade Repetition and Inattention Associated with Neurofibromatosis Type 1

    ERIC Educational Resources Information Center

    Coude, Francois X.; Mignot, Claire; Lyonnet, Stanislas; Munnich, Arnold

    2007-01-01

    Objective: The authors analyze the occurrence of grade repetition and inattention in children diagnosed with neurofibromatosis type 1 (NF1). Method: The participant group consisted of 310 patients with NF1 and a control group of 242 individuals. The number of grade repetitions for each participant during his or her time in elementary, middle, and…

  3. Cognitive Profile of Neurofibromatosis Type 1: Rethinking Nonverbal Learning Disabilities

    ERIC Educational Resources Information Center

    Cutting, Laurie E.; Clements, Amy M.; Lightman, Andrea D.; Yerby-Hammack, Pamula D.; Denckla, Martha Bridge

    2004-01-01

    The cognitive profiles of children with Neurofibromatosis Type 1 (NF-1) have many similarities to those observed in learning disabilities in the general school population, as well as some distinct features. Approximately 30-65 percent of children with NF-1 have learning disabilities; most commonly, they have language and reading disabilities,…

  4. Brief Report: The Association of Neurofibromatosis Type 1 and Autism.

    ERIC Educational Resources Information Center

    Williams, P. Gail; Hersh, Joseph H.

    1998-01-01

    A study reviewed neurodevelopment evaluations of 74 patients with Neurofibromatosis Type 1 (NF1) to determine if an association between NF1 and autism exists. Three patients had an additional diagnosis of autism. Findings also a high incidence of learning disabilities, speech and language delays, motor deficits, and attention problems in patients.…

  5. Articulation in Schoolchildren and Adults with Neurofibromatosis Type 1

    ERIC Educational Resources Information Center

    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…

  6. Neurofibromatosis Type 2 Presenting with Oculomotor Ophthalmoplegia and Distal Myopathy

    PubMed Central

    Tevaraj, Jessica Mani Penny; Mohd Noor, Raja Azmi; Yaakub, Azhany

    2016-01-01

    Neurofibromatosis type 2 usually presents with bilateral acoustic schwannomas. We highlight the rare presentation of neurofibromatosis initially involving third nerve. A 23-year-old Malay female presented with left eye drooping of the upper lid and limitation of upward movement for 8 years. It was associated with right-sided body weakness, change in voice, and hearing disturbance in the right ear for the past 2 years. On examination, there was mild ptosis and limitation of movement superiorly in the left eye. Both eyes had posterior subcapsular cataract. Fundoscopy showed generalised optic disc swelling in both eyes. She also had palsy of the right vocal cord, as well as the third and eighth nerve. There was wasting of the distal muscles of her right hand, with right-sided decreased muscle power. Pedunculated cutaneous lesions were noted over her body and scalp. MRI revealed bilateral acoustic and trigeminal schwannomas with multiple extra-axial lesions and intradural extramedullary nodules. Patient was diagnosed with neurofibromatosis type 2 and planned for craniotomy and tumour debulking, but she declined treatment. Neurofibromatosis type 2 may uncommonly present with isolated ophthalmoplegia, so a thorough physical examination and a high index of suspicion are required to avoid missing this condition. PMID:27738538

  7. 17q Inversion involving the neurofibromatosis type one locus in a family with neurofibromatosis type one

    SciTech Connect

    Asamoah, A.; North, K.; Wagstaff, J.

    1995-08-14

    We report a family with a paracentric inversion of the long arm of chromosome 17 [inv(17)(q11.2q25.1)] and neurofibromatosis type one (NF1). The family was ascertained because of NF1 and multiple miscarriages. Fluorescence in situ hybridization using cosmid probes from opposite ends of the NF1 gene confirmed that the inversion gel electrophoresis we have found that the inversion separates cDNA probes FB5D and AE25, which are normally adjacent to one published report of a gross chromosomal rearrangement responsible for NF1. The features in this family are typical for NF1, and are not unusually severe. 26 refs., 5 figs.

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

    PubMed

    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.

  9. Characterization of naturally occurring cutaneous neurofibromatosis in Holstein cattle. A disorder resembling neurofibromatosis type 1 in humans.

    PubMed Central

    Sartin, E. A.; Doran, S. E.; Riddell, M. G.; Herrera, G. A.; Tennyson, G. S.; D'Andrea, G.; Whitley, R. D.; Collins, F. S.

    1994-01-01

    Neurofibromatosis in cattle is typically a noncutaneous disease. A small group of cows in a Holstein dairy herd developed cutaneous neurofibromatosis. This unique condition was investigated and compared with neurofibromatosis type 1 (NF1) in humans. All cutaneous lesions but one were consistent with neurofibromas in noncutaneous sites in cattle and neurofibromas in patients with NF1. One bovine lesion was classified as a neurofibrosarcoma. Immunohistochemistry and electron microscopy supported Schwannian differentiation in benign and malignant lesions. Linkage analysis with a polymorphism in the bovine NF1 gene confirmed that two affected animals from the same sire inherited the same paternal NF1 allele. Bovine cutaneous neurofibromatosis is a naturally occurring disease in this group of animals, characterized by skin tumors morphologically identical to those of NF1. An informative polymorphism at the NF1 locus of two animals and their sire suggests this disorder may be caused by hereditary mutations at the bovine NF1 locus. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:7977647

  10. Ruptured profunda femoris aneurysm secondary to neurofibromatosis: vascular involvement in an unusual location.

    PubMed

    Emrecan, Bilgin; Onem, Gokhan; Susam, Ibrahim

    2010-01-01

    Neurofibromatosis is an autosomal dominant genetic disease characterized by abnormal growth that involves tissues of mesodermal and neuroectodermal origin. Aneurysms are rarely seen in peripheral arteries. This report presents a case of ruptured arterial aneurysm secondary to neurofibromatosis; the lesion occurred in the profunda femoris artery, a highly unusual location. Treatment of patients with ruptured arterial aneurysm secondary to neurofibromatosis may be interventional or surgical. In this case, a surgical approach was successful.

  11. The Risk and Clinical/Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

    DTIC Science & Technology

    2012-10-01

    Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1 PRINCIPAL INVESTIGATOR: Xia Wang, M.D., Ph.D...Women with Neurofibromatosis Type 1” 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0671 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Xia Wang...Several reports from England and the United States have described increased breast cancer occurrence in women affected with Neurofibromatosis type 1

  12. Type 1 neurofibromatosis and pulmonary hypertension: a report of two cases and a review

    PubMed Central

    Malviya, Amit; Mishra, Sundeep; Kothari, Shyam S

    2012-01-01

    Pulmonary hypertension in type 1 neurofibromatosis is not well known and was previously attributed to diffuse fibrosing alveolitis and parenchymal tumours. More recently, cases of severe pulmonary hypertension due to pulmonary vasculopathy have been described. Involvement of vascular beds, both large and medium calibre vessels, but not pulmonary vasculature, in type 1 neurofibromatosis is well known. The authors describe two such cases and briefly review the literature. Pulmonary arterial hypertension in neurofibromatosis warrants further studies. PMID:27326022

  13. Magnetic resonance neurographic confirmation of extensive Plexiform neurofibroma in neurofibromatosis-1 presenting as ambiguous genitalia

    PubMed Central

    Kumar, Ishan; Verma, Ashish; Ojha, Ritu; Aggarwal, Priyanka; Shukla, Ram C; Srivastava, Arvind

    2016-01-01

    Genitourinary involvement of neurofibromatosis is uncommon and genital neurofibromatosis is even rarer. Involvement of clitoris by neurofibroma can lead to clitoromegaly masquerading as a male penis. We report such a case of ambiguous genitalia in a 7-year-old female child presenting with clitoromegaly since birth, in which magnetic resonance imaging (MRI) revealed the presence of extensive neurofibromatosis in the clitoris and lumbosacral regions. We emphasize the central role of MRI in evaluation of hormonal and non-hormonal causes of ambiguous genitalia. We further discuss the merits of including MR neurography in the imaging protocol for comprehensive delineation of neurofibromatosis. PMID:27857458

  14. The spectrum of pheochromocytoma in hypertensive patients with neurofibromatosis

    SciTech Connect

    Kalff, V.; Shapiro, B.; Lloyd, R.; Sisson, J.C.; Holland, K.; Nakajo, M.; Beierwaltes, W.H.

    1982-11-01

    We have found an appreciable number of pheochromocytomas in patients with neurofibromatosis and concurrent hypertension (ten of 18 cases). At diagnosis, the patient age range was 15 to 62 years, the clinical appearance of the neurofibromatosis did not predict who would and who would not have pheochromocytomas, but the age at diagnosis was helpful in that our younger patients tended to have causes of hypertension other than pheochromocytoma. However, several causes of hypertension may coexist. The biochemical findings were highly diagnostic. The pheochromocytomas secreted epinephrine as well as norepinephrine and resided in or next to the adrenal gland. Where pheochromocytoma is the cause of hypertension, its resection generally results in a better control of hypertension than that obtained in patients whose BPs were elevated from other unknown causes.

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

    PubMed

    Thomas, Anna K; Egelhoff, John C; Curran, John G; Thomas, Bobby

    2016-03-01

    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.

  16. Coincidence of GIST and pancreatic endocrine neoplasm in neurofibromatosis.

    PubMed

    Dominguez-Comesaña, Elias; Tome-Espiñeiro, Catherine; Ulla-Rocha, Jose L; Lorenzo-Lorenzo, Isabel; Lede-Fernandez, Angel; Portela-Serra, Jose L

    2011-09-01

    Carcinoids of the ampulla of Vater are infrequent tumors of which a quarter of cases have been detected in patients with type I neurofibromatosis. This hereditary disease is also associated with gastrointestinal stromal tumors (GIST). However, the coincidence of these three entities together have only been formerly detected in five cases. A 53 year-old female patient, diagnosed with type I neurofibromatosis, with a malignant carcinoid of ampulla of Vater and multiple gastrointestinal stromal tumors in the duodenum and jejunum, was treated with total pancreatectomy and the excision of her intestinal tumors. Five-years on, a follow-up showed the patient to be well, and free from tumor recurrence. The coexistence of an ampullary carcinoid tumor, GIST and neurofibramatosis is very rare. Radical curative surgical resection is a good treatment option, but the optimal management of this is not yet well established.

  17. [Esthetic otoplasty in subjects presenting with facial neurofibromatosis].

    PubMed

    Kriukov, A I; Kariakina, I A

    2012-01-01

    The results of surgical treatment of a woman presenting with facial and cervical soft-tissue neurofibromatosis and a concomitant auricular defect are presented. The otoplasty was performed by means of sectoral dissection of the auricular skeleton as described by Trendelenburg with the subsequent correction of the surrounding facial and cervical tissues. Much attention is given to the step by step procedure of correction of the auricular deformity and the surrounding facial and cervical tissues in the patients with this pathology.

  18. Tibial Bowing and Pseudarthrosis in Neurofibromatosis Type 1

    DTIC Science & Technology

    2013-04-01

    observed in 5% of children with neurofibromatosis type 1 ( NF1 ), typically identified in infancy. The majority of NF1 individuals with tibial bowing...will sustain a fracture that will not heal (i.e. pseudarthrosis) resulting in multiple surgeries, poor limb function, and amputation. Some NF1 ...pseudarthrosis and better understand its pathophysiology. We have begun recruitment and assessed many individuals with NF1 with and with tibial bowing. QUS

  19. Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1

    PubMed Central

    Gundogdu, Baris; Yolbas, Servet; Yildirim, Ahmet; Gonen, Murat

    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 and NF1. PMID:27597922

  20. [Small bowel neurofibromatosis in Von Recklinghausen's disease. A rare cause of emergency surgery].

    PubMed

    Ben Achour, Jamel; Hani, Mohamed Aziz; Bouasker, Ibtissem; Guesmi, Fethi; Zoghlami, Ayoub; Najah, Nabil

    2003-11-01

    Two cases of small bowel neurofibromatosis in patients with Von Recklinghausen's disease are reported. Diagnosis of small bowel neurofibromatosis was made on the occasion of a complication for the two cases. We insist on the difficulty of diagnosis as well as in presence or not of complications. Treatment of these most often benign tumours remains surgical based on a segmental small bowel resection.

  1. Parathyroid adenoma associated with neurofibromatosis: Correlative scintigraphic and magnetic resonance imaging

    SciTech Connect

    Vogelzang, P.J.; Oates, E.; Bankoff, M.S.

    1989-03-01

    Correlative imaging by dual-isotope thallium/technetium subtraction scintigraphy, computed tomography, and magnetic resonance imaging demonstrated a pathologically proven parathyroid adenoma in a 62-year-old man with known neurofibromatosis, who presented with hypercalcemia and an elevated parathormone level. The association between neurofibromatosis and primary hyperparathyroidism is discussed.

  2. Von recklinghausen neurofibromatosis-pachydermatocele causing lower limb gigantism: a case report.

    PubMed

    Rekha, Arcot; Gopalan, T R

    2006-03-01

    Gigantism of the lower limb can occur because of plexiform neurofibromas. This condition is seen with café au lait patches and multiple neurofibromatosis in this case of von Recklinghausen neurofibromatosis. We report our patient and review literature of this uncommon condition.

  3. Identification of Growth Hormone Receptor in Plexiform Neurofibromas of Patients with Neurofibromatosis Type 1

    PubMed Central

    Cunha, Karin Soares Gonçalves; Barboza, Eliane Porto; da Fonseca, Eliene Carvalho

    2008-01-01

    OBJECTIVE The aim of this study was to investigate the presence of growth hormone receptor in plexiform neurofibromas of neurofibromatosis type 1 patients. INTRODUCTION The development of multiple neurofibromas is one of the major features of neurofibromatosis type 1. Since neurofibromas commonly grow during periods of hormonal change, especially during puberty and pregnancy, it has been suggested that hormones may influence neurofibromatosis type 1 neurofibromas. A recent study showed that the majority of localized neurofibromas from neurofibromatosis type 1 patients have growth hormone receptor. METHODS Growth hormone receptor expression was investigated in 5 plexiform neurofibromas using immunohistochemistry. RESULTS Four of the 5 plexiform neurofibromas were immunopositive for growth hormone receptor. CONCLUSION This study suggests that growth hormone may influence the development of plexiform neurofibromas in patients with neurofibromatosis type 1. PMID:18297205

  4. [A case of nerve angiomatosis associated with neurofibromatosis type I].

    PubMed

    von Campe, A; Omaren, H; Troeger, M; Meuli-Simmen, C

    2012-12-01

    We present the case of a patient suffering from Neurofibromatosis type I (NF-1) with acute, very painful neuropathy of the right lower extremity. The preoperative electro neuro- physiological study showed an impaired function of the peroneal nerve. The MRI revealed an extended diffuse plexiform tumour of the sciatic nerve and at thigh level. Biopsies showed marked diffuse angiomatosis within the sciatic nerve.To our knowledge, this is the first description of an intraneural vascular malformation in NF-1.Treatment of such an entity is a challenge and must be individually defined.

  5. Neuropsychological impairments in elderly Neurofibromatosis type 1 patients.

    PubMed

    Costa, Danielle de Souza; de Paula, Jonas Jardim; de Rezende, Nilton Alves; Rodrigues, Luiz Oswaldo Carneiro; Malloy-Diniz, Leandro Fernandes; Romano-Silva, Marco Aurélio; Miranda, Débora Marques de

    2014-04-01

    Cognitive performance is compromised in Neurofibromatosis type 1 (NF1) patients, but neuropsychological data including elderly NF1 are extremely sparse. We compared the cognitive performance of a small elderly NF1 group (n = 5) with an age-matched healthy control group (n = 49). NF1 group performed worse than control group on a global cognitive impairment task, verbal working memory, and visuospatial functioning. The results suggest that cognitive impairment is an important feature of NF1 across lifespan, including elderly individuals. Future studies approaching the NF1 cognitive profile might benefit from looking at the mechanisms linked to the age-related aspects of cognitive decline.

  6. The range of multiple sclerosis associated with neurofibromatosis type 1

    PubMed Central

    Perini, P; Gallo, P

    2001-01-01

    Multiple sclerosis associated with neurofibromatosis type 1 (NF1) is a very rare event. Seven patients with multiple sclerosis and NF1 are described in the literature, and all were reported to have the primary progressive form of multiple sclerosis. Three new patients with NF1 that developed multiple sclerosis are described and it is shown that the range of multiple sclerosis associated with NF1 includes the relapsing forms of the disease. The risk of having both NF1 and multiple sclerosis in north east Italy is higher than would be expected based on the prevalence rates of the two diseases.

 PMID:11606684

  7. Neurofibromatosis clinical presentations: A report of two cases

    PubMed Central

    Kitchen, Robert G; Waddell, Brad M; Willson, Robert D

    1987-01-01

    Neurofibromatosis (NFT) is an autosomal dominant disorder. Several distinctive clinical features may be discovered in the presence of the disease, including ècafé au laité spots, cutaneous neurofibromas, axillary freckling, Lisch nodules, and a positive familial history. Chiropractic management of this condition should include early recognition, appropriate supportive referral and symptomatic treatment of accompanying biomechanical dysfunctions. Early diagnosis will not only permit appropriate assessment, but will allow for vital genetic counselling. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7

  8. Extracranial Vertebral Artery Involvement in Neurofibromatosis Type I

    PubMed Central

    Pereira, V.M.; Geiprasert, S.; Krings, T.; Caldas, J.G.M.P.; Toulgoat, F.; Ozanne, A.; Mercier, P.; Lasjaunias, P. L.

    2007-01-01

    Summary Neurofibromatosis type 1 (NF-1) is one of the most common inherited diseases and as an autosomal dominant genetic disorder results from NF-1 gene mutation with 100% penetration and wide phenotypic variability. The disease can involve a wide variety of tissues derived from all three embryonic layers. NF-1 vasculopathy has been described primarily in peripheral arteries, but arteries supplying the CNS may also be involved. Of those, extracranial vertebral involvement is the commonest and most important. A series of four patients with NF-1 and vascular disease of the vertebral artery is described with a review of the pathophysiology, vascular phenotypes, their management and the pertinent literature. PMID:20566100

  9. Spontaneous hemothorax associated with neurofibromatosis type I: A review of the literature

    PubMed Central

    Pulivarthi, Swaroopa; Simmons, Byron; Shearen, John; Gurram, Murali Krishna

    2014-01-01

    Neurofibromatosis is generally a benign disease, but has the potential for rare and fatal complications, such as spontaneous hemothorax. We report a case of massive hemothorax due to neurofibroma in a 49-year-old woman with neurofibromatosis type 1. The configuration of the radiological opacity and frank blood withdrawn on thoracentesis should suggest the diagnosis of hemothorax in a patient with neurofibromatosis. Surgical treatment for hemothorax is limited by arterial fragility and the prognosis is relatively poor. Any evidence of aneurysmal disease in the thoracic vessels should be aggressively managed percutaneously by coil embolization to prevent future rupture. PMID:25002768

  10. A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene.

    PubMed Central

    Ars, E; Kruyer, H; Gaona, A; Casquero, P; Rosell, J; Volpini, V; Serra, E; Lázaro, C; Estivill, X

    1998-01-01

    Spinal neurofibromatosis (SNF) has been considered to be an alternative form of neurofibromatosis in which spinal cord tumors are the main clinical characteristic. Familial SNF has been reported, elsewhere, in three families-two linked to markers within the gene for neurofibromatosis type 1 (NF1) and the other not linked to NF1-but no molecular alterations have been described in these families. We describe a three-generation family that includes five members affected by SNF. All the affected members presented multiple spinal neurofibromas and café au lait spots, one member had cutaneous neurofibromas, and some members had other signs of NF1. Genetic analysis, performed with markers within and flanking the NF1 gene, showed segregation with the NF1 locus. Mutation analysis, performed with the protein-truncation test and SSCP/heteroduplex analysis of the whole coding region of the NF1 gene, identified a frameshift mutation (8042insA) in exon 46, which should result in a truncated NF1 protein. The 8042insA mutation was detected in all five family members with the SNF/NF1 phenotype. To our knowledge, this is the first time that a mutation in the NF1 gene has been associated with SNF. The clinical homogeneity in the severity of the disease among the affected members of the family, which is unusual in NF1, suggests that a particular property of the NF1 mutation described here, a gene closely linked to NF1, or posttranscriptional events are involved in this severe neurological phenotype. PMID:9529361

  11. Indocyanine Green Angiographic Findings of Obscure Choroidal Abnormalities in Neurofibromatosis

    PubMed Central

    Byun, Yong Soo

    2012-01-01

    We report two cases of choroidal neurofibromatosis, detected with the aid of indocyanine green angiography (ICGA) in patients with neurofibromatosis (NF)-1, otherwise having obscure findings based on ophthalmoscopy and fluoresceine angiography (FA). In case 1, the ophthalmoscopic exam showed diffuse bright or yellowish patched areas with irregular and blunt borders at the posterior pole. The FA showed multiple hyperfluorescent areas at the posterior pole in the early phase, which then showed more hyperfluorescence without leakage or extent in the late phase. The ICGA showed diffuse hypofluorescent areas in both the early and late phases, and the deep choroidal vessels were also visible. In case 2, the fundus showed no abnormal findings, and the FA showed weakly hypofluorescent areas with indefinite borders in both eyes. With the ICGA, these areas were more hypofluorescent and had clear borders. Choroidal involvement in NF-1 seems to occur more than expected. In selected cases, ICGA is a useful tool to be utilized when an ocular examination is conducted in a patient that has no definite findings based on the ophthalmoscope, B-scan, or FA tests. PMID:22670083

  12. Orthopaedic manifestations of neurofibromatosis in children: an update.

    PubMed

    Vitale, Michael G; Guha, Abhijit; Skaggs, David L

    2002-08-01

    Neurofibromatosis is one of the most common genetic disorders affecting mankind. Despite extensive basic science research, the diagnosis still is based largely on well-defined clinical criteria, which often present gradually during childhood. Approximately 50% of patients have significant musculoskeletal manifestations, with scoliosis and congenital pseudarthrosis of the tibia most common. Approximately 20% of children with Type I neurofibromatosis present with scoliosis with or without the classic dystrophic features, such as vertebral scalloping and rib penciling. Dystrophic curves portend rapid progression and require early fusion. Surgical treatment often is challenging because of the common presence of neurofibromas adjacent to the spinal cord, significant multiplanar deformity, and poor bone quality. Congenital pseudarthrosis of the tibia also continues to present significant difficulties. The use of a brace is the mainstay of early treatment, whereas intramedullary rodding commonly is used for operative fixation. Grafting of the free fibula and correction using techniques of distraction and compression histiogenesis with Ilizarov fixators have been reported for refractory cases with varying degrees of success. Multiple heroic, operative attempts may have a tremendous toll on the quality of life of affected children through their early childhood. In addition to these and other distinctive musculoskeletal lesions, affected children often suffer from various medical problems.

  13. Neurofibromatosis in children: the role of the orthopaedist.

    PubMed

    Crawford, A H; Schorry, E K

    1999-01-01

    Type 1 neurofibromatosis (NF-1), also known as von Recklinghausen disease, is one of the most common human single-gene disorders, affecting at least 1 million persons throughout the world. It encompasses a spectrum of multifaceted disorders and may present with a wide range of clinical manifestations, including abnormalities of the skin, nervous tissue, bones, and soft tissues. The condition can be conclusively diagnosed when two of seven criteria established by the National Institutes of Health Consensus Development Conference are met. Most children with NF-1 have no major orthopaedic problems. For those with musculoskeletal involvement, the most important issue is early recognition. Spinal deformity, congenital tibial dysplasia (congenital bowing and pseudarthrosis), and disorders of excessive bone and soft-tissue growth are the three types of musculoskeletal manifestations that require evaluation. Statistics gathered from the Cincinnati Children's Hospital Neurofibromatosis Center database show the incidence of spinal deformity in children with NF-1 to be 23.6%; pectus deformity, 4.3%; limb-length inequality, 7.1%; congenital tibial dysplasia, 5.7%; hemihypertrophy, 1.4%; and plexiform neurofibromas, 25%. The orthopaedic complications can be managed, but only rarely are they cured.

  14. Cerebellar Hypoplasia and Dysmorphia in Neurofibromatosis Type 1.

    PubMed

    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.

  15. Perinatal neurofibromatosis: two case reports and review of the literature.

    PubMed

    Isaacs, Hart

    2010-04-01

    Neurofibromatosis-1 (NF-1) is an autosomal-dominant genetic disorder with many different manifestations. Some may have evidence of the disease at birth. A 66-year (1942 to 2008) retrospective review of 36 patients including 7 fetuses and 29 neonates with NF-1 was performed. Only patients with NF-1 lesions detected before birth by imaging or noted in the first month of life were entered into the review. There was a strongly positive family history of the disease of 70%. The most common presenting findings in the fetus were hydrops, macrocephaly, and thickened neck soft tissues and those in the neonate were café au lait macules, skin nodules, and buphthalmos. Survivors developed serious sequelae (e.g., progressive growth of neurofibromas within the neck and mediastinum leading to increasing airway obstruction and death; an enlarging, proptotic, and glaucomatous eye; and occurrence of brain and malignant nerve sheath tumors). Congenital generalized (disseminated) neurofibromatosis was associated with a poor prognosis, with a mortality rate of 92%. Survival rates for patients detected before and after birth were 28% and 62%, respectively. The overall survival was 20/36 or 56%.

  16. Grade 4 spondylolisthesis of the L5 vertebra associated with dural ectasia in neurofibromatosis.

    PubMed

    Modi, H N; Srinivasalu, S; Suh, S W; Yang, J H

    2009-08-01

    Spondylolisthesis associated with neurofibromatosis is rare, and only 12 cases have been reported so far. However, only one report of grade 4 spondylolisthesis with neurofibromatosis has been reported in the literature. A 15-year-old boy with neurofibromatosis was admitted for back pain and neurological claudication. Radiograph showed grade 4 spondylolisthesis of the L5 vertebra with scalloping of the L4-L5 vertebrae. L4-L5 laminectomy, reduction, L3-S1 posterior instrumentation and fusion were performed. The reduction of the spondylisthesis was done entirely from the posterior approach using pedicle screws. Radiography at four months showed a broken S1 screw with a loss of reduction. The patient was re-operated on, to provide additional stability with pelvic fixation. He was pain-free with a good fusion at the two-year follow-up. Adequate posterior stabilisation with fusion gives good results in grade 4 spondylolisthesis associated with neurofibromatosis and dural ectasia.

  17. Malignant transformation of neurofibromas at multiple sites in a case of neurofibromatosis.

    PubMed Central

    Leslie, M. D.; Cheung, K. Y.

    1987-01-01

    A patient with classical neurofibromatosis is reported in whom malignant transformation of neurofibromas at multiple sites occurred, leading to a fatal outcome. One of these malignant tumours developed within the thyroid gland. Images Figure 1 Figure 2 PMID:3118347

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

    PubMed

    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.

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

    PubMed

    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.

  20. Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-10-1-0469 TITLE: Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis...31Jul2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER " Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis." 5b...an existing genetic test used to predict scoliosis progression in adolescent idiopathic scoliosis could also identify dystrophic scoliosis in NF1

  1. Description of prosthetic treatment in case of neurofibromatosis in the course of Recklinghausen disease. Case course.

    PubMed

    Ey-Chmielewska, Halina; Sobolewska, Ewa; Fraczak, Bogumiła

    2007-01-01

    Neurofibromatosis is a hereditary autosomal predominating disease occuring in one out of every 2000 or 3300 alive births. The classical form of neurofibromatosis was described by von Recklinghausen in 1882. The disease is a gene mutation, where the anomalies affect mesoderm and neuroectoderm. The paper presents the therapeutic treatment method for the case of lacking teeth restoration in a patient diagnosed with known form ofneurofibromatosis NF-1 in Recklinghausen disease.

  2. Perineural fibrous thickening within the dental pulp in type 1 neurofibromatosis: a case report.

    PubMed

    Curtin, J P; McCarthy, S W

    1997-10-01

    A case of type 1 neurofibromatosis is presented that illustrates oral manifestations and their role in the diagnosis of this condition. The oral lesions may be overlooked in the diagnosis of intraoral swellings. This case documents the finding of perineural fibrous thickening within the dental pulp. Such changes may indicate pulpal involvement in neurofibromatosis and the effect of a genetically transmitted disorder upon the pulp.

  3. Face Transplant in an Advanced Neurofibromatosis Type 1 Patient.

    PubMed

    Krakowczyk, Łukasz; Maciejewski, Adam; Szymczyk, Cezary; Oleś, Krzysztof; Półtorak, Stanisław

    2017-01-31

    BACKGROUND The human face is a one-of-a-kind structure with unique morphology, complexity, and function, in which different subunits are not even similar to other parts of the body. Therefore, extended complex deficits of the face are usually difficult to reconstruct, and autologous tissue restoration is generally not able to give a satisfactory aesthetic and functional outcome. The main goal of face allotransplantation is to restore symmetry, contour, and appearance as well as function of the face, especially control of orbicularis oculi and oris muscle physiology. We present the case of a total face transplant in an advanced neurofibromatosis type 1 patient - the second face transplant in Poland. CASE REPORT The recipient was a 28-year-old female with neurofibromatosis type I limited to the head region. During 24 years she underwent more than 35 surgical procedures, but for the last 3 years a significant decrease of her functionality and appearance was observed, including serious problems with speech, eating, and vision. In December 2013 she was qualified for a face transplant procedure. When the donor was found, she was matched on several clinical and biochemical characteristics including negative T and B cell cross-matching. Similarly, the transplantation procedure was done using two connected operating rooms; in the first, the donor's face was harvested, and in the second, the recipient's face was prepared - the tumor mass was resected and vascular and nervous structures were prepared. Due to the extension and complexity of the potential defect, more than 75% of head soft tissues were harvested including both auriculae, left and right eyelids, and scalp down to the occipital lower line. CONCLUSIONS Our case showed that neurofibromatosis is a real indication for a face transplantation procedure. Also, the results of rehabilitation, quality of life, motor and sensory recovery, and physiological status were comparable, showing that face transplantation based on

  4. Autism spectrum disorder profile in neurofibromatosis type I.

    PubMed

    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.

  5. Presymptomatic genetic testing in children for neurofibromatosis 2.

    PubMed

    Twomey, John G; Bove, Catherine; Cassidy, Deborah

    2008-06-01

    Genetic testing in children, when there is a question of whether or not there is a clear medical benefit that will accrue to the child, is a controversial topic within the health care community. A convenience sample of 10 parents from nine families who had made the decision whether or not to test their children for the neurofibromatosis 2 gene mutation was asked in interviews to describe why they made their choice about presymptomatic testing for this late-onset disease. Findings from a narrative analysis revealed how the nine parents who tested or intended to test their young children saw the decision as a pathway to knowledge that would help the family unit. All parents interviewed noted that their decision was informed by their health team and was not difficult to make. Implications of these findings for bioethical analysis are presented.

  6. [Severe pulmonary involvement in the course of type 1 neurofibromatosis].

    PubMed

    Martignac, B; Gagnadoux, F; Trzepizur, W; Beneton, N; Vinchon, F; Paris, A; Montani, D; Goupil, F

    2014-09-01

    Type 1 neurofibromatosis (NF1) is a hereditary disease inherited as an autosomal dominant. Respiratory involvement is rare. We report the case of a woman suffering from NF1 with mutation of the corresponding gene and with respiratory involvement combining diffuse parenchymatous lesions, severe precapillary pulmonary hypertension and an enlarging, spiculated pulmonary nodule, very suspicious of malignancy, though histological examination was not possible on account of the patient's poor respiratory function. There was progressive deterioration of the patient's respiratory condition, leading to death, despite the introduction of oral therapy combining a phosphodiesterase 5 inhibitor and an endothelin receptor antagonist. Our case illustrates the development of multiple severe respiratory pathologies in the setting of NF1. The specific contribution of the NF1 gene mutation in the pathophysiology of these different pulmonary manifestations needs to be examined in detail.

  7. Screening children with neurofibromatosis type 1 for autism spectrum disorder.

    PubMed

    Tinker, Jade; Carbone, Paul S; Viskochil, David; Mathiesen, Amber; Ma, Khe-Ni; Stevenson, David A

    2014-07-01

    Autism spectrum disorder (ASD) is reported to be increased in neurofibromatosis type 1 (NF1), but it's unknown if ASD screening tools are sensitive and specific for NF1. This study compared the rate at which children with NF1 screen-positive for two ASD screening tools [Modified Checklist for Autism in Toddlers (M-CHAT) and Childhood Autism Spectrum Test (CAST)] to the screen-positive rate of the general population. A retrospective cross-sectional observational design to investigate the association between children with NF1 and at risk status for ASD was used. Medical records of children between 16 months and 11 years of age seen in an NF Clinic were reviewed for an ASD screening questionnaire. There were no statistically significant differences in the screen-positive rate for ASD in NF1 compared to published controls, but mean CAST scores were higher in NF1.

  8. Mapping neurofibromatosis 1 homologous loci by fluorescence in situ hybridization

    SciTech Connect

    Viskochil, D.; Breidenbach, H.H.; Cawthon, R.

    1994-09-01

    Neurofibromatosis 1 maps to chromosome band 17q11.2 and the NF1 gene is comprised of 59 exons that span approximately 335 kb of genomic DNA. In order to further analyze the structure of NF1 from exons 2 through 27b, we isolated a number of cosmid and bacteriophage P-1 genomic clones using NF1-exon probes under high-stringency hybridization conditions. Using tagged, intron-based primers and DNA from various clones as a template, we PCR-amplified and sequenced individual NF1 exons. The exon sequences in PCR products from several genomic clones differed from the exon sequence derived from cloned NF1 cDNAs. Clones with variant sequences were mapped by fluorescence in situ hybridization under high-stringency conditions. Three clones mapped to chromosome band 15q11.2, one mapped to 14q11.2, one mapped to both 2q14.1-14.3 and 14q11.2, one mapped to 2q33-34, and one mapped to both 18q11.2 and 21q21. Even though some PCR-product sequences retained proper splice junctions and open reading frames, we have yet to identify cDNAs that correspond to the variant exon sequences. We are now sequencing clones that map to NF1-homologous loci in order to develop discriminating primer pairs for the exclusive amplification of NF1-specific sequences in our efforts to develop a comprehensive NF1 mutation screen using genomic DNA as template. The role of NF1-homologous sequences may play in neurofibromatosis 1 is not clear.

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

    SciTech Connect

    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.

  10. Bilateral internal auditory canal gangliogliomas mimicking neurofibromatosis Type II

    PubMed Central

    Hooten, Kristopher G.; Oliveria, Seth F.; Sadrameli, Saeed S.; Gandhi, Shashank; Yachnis, Anthony T.; Lewis, Stephen B.

    2016-01-01

    Background: Gangliogliomas are rare low grade, typically well-differentiated, tumors that are composed of mature ganglion cells and neoplastic glial cells. These tumors can appear at virtually any location along the neuroaxis but classically occur in the temporal lobe of young patients. In a small number of cases, gangliogliomas have presented as masses in the brainstem or involving cranial nerves. With the exception of vestibular schwannomas, bilateral tumors in the region of the internal auditory canal (IAC) or cerebellopontine angle (CPA) are exceedingly rare. Case Description: We report a case of a 58-year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow-up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. Description: We report a case of a 58-year-old male who presented with hearing loss, tinnitus, and vertigo. Initial magnetic resonance imaging revealed bilateral nonenhancing IAC/CPA tumors. Based on this finding, a presumptive diagnosis of neurofibromatosis Type II was made, which was initially managed conservatively with close observation. He returned for follow-up with worsening vertigo and tinnitus, thus prompting the decision to proceed with surgical resection of the symptomatic mass. Intriguingly, pathological study demonstrated a WHO Grade I ganglioglioma. Conclusion: This is the first reported case of bilateral IAC/CPA gangliogliomas. When evaluating bilateral IAC/CPA lesions with unusual imaging characteristics, ganglioglioma should be included in the differential diagnosis. PMID:27127704

  11. Molecular genetics of neurofibromatosis type 1 (NF1).

    PubMed Central

    Shen, M H; Harper, P S; Upadhyaya, M

    1996-01-01

    Neurofibromatosis type 1 (NF1), also called von Recklinghausen disease or peripheral neurofibromatosis, is a common autosomal dominant disorder characterised by multiple neurofibromas, café au lait spots, and Lisch nodules of the iris, with a variable clinical expression. The gene responsible for this condition, NF1, has been isolated by positional cloning. It spans over 350 kb of genomic DNA in chromosomal region 17q11.2 and encodes an mRNA of 11-13 kb containing at least 59 exons. NF1 is widely expressed in a variety of human and rat tissues. Four alternatively spliced NF1 transcripts have been identified. Three of these transcript isoforms (each with an extra exon: 9br, 23a, and 48a, respectively) show differential expression to some extent in various tissues, while the fourth isoform (2.9 kb in length) remains to be examined. The protein encoded by NF1, neurofibromin, has a domain homologous to the GTPase activating protein (GAP) family, and downregulates ras activity. The identification of somatic mutations in NF1 from tumour tissues strongly supports the speculation that NF1 is a member of the tumour suppressor gene family. Although the search for mutations in the gene has proved difficult, germline mutation analysis has shown that around 82% of all the fully characterised NF1 specific mutations so far predict severe truncation of neurofibromin. Further extensive studies are required to elucidate the gene function and the mutation spectrum. This should then facilitate the molecular diagnosis and the development of new therapy for the disease. PMID:8825042

  12. Giant café-au-lait macule in neurofibromatosis 1: a type 2 segmental manifestation of neurofibromatosis 1?

    PubMed

    Yang, Chao-Chun; Happle, Rudolf; Chao, Sheau-Chiou; Yu-Yun Lee, Julia; Chen, WenChieh

    2008-03-01

    Type 2 segmental manifestation of autosomal dominant dermatoses refers to pronounced segmental lesions superimposed on the ordinary nonsegmental phenotype, indicating loss of heterozygosity occurring at an early stage of embryogenesis. We describe a 20-year-old Taiwanese woman with typical lesions of neurofibromatosis type 1 (NF1) in the form of characteristic café-au-lait spots, neurofibromas, axillary freckling and Lisch nodules. In addition, a giant garment-like or "bathing-trunk" café-au-lait macule involved the lower half of the trunk, the buttocks, and parts of the thighs, being superimposed on the ordinary smaller spots of NF1. This large café-au-lait macule may be best explained as an example of type 2 segmental NF1. A novel mutation (3009delG) in exon 23 was also identified in this patient, which has not yet been described in sporadic and familial NF1.

  13. Is NF-1 gene deletion the molecular mechanism of neurofibromatosis type 1 with destinctive facies?

    SciTech Connect

    Leppig, K.A.; Stephens, K.G.; Viskochill, D.; Kaplan, P.

    1994-09-01

    We have studied a patient with neurofibromatosis type 1 and unusual facial features using fluorescence in situ hybridization (FISH) and found that the patient had a deletion that minimially encompasses exon 2-11 of the NF-1 gene. The patient was one of two individuals initially described by Kaplan and Rosenblatt who suggested that another condition aside from neurofibromatosis type 1 may account for the unusual facial features observed in these patients with neurofibromatosis type 1. FISH studies were performed using a P1 clone probe, P1-9, which contains exons 2-11 of the NF-1 gene on chromosomes prepared from the patients. In all 20 metaphase cells analyzed, one of the chromosome 17 homologues was deleted for the P1-9 probe. Therefore, this patient had neurofibromatosis type 1 and unusual facial features as the result of a deletion which minimally includes exons 2-11 of the NF-1 gene. The extent of the deletion is being mapped by FISH and somatic cell hybrid analysis. The patient studied was a 7-year-old male with mild developmental delays, normal growth parameters, and physical findings consistent with neurofibromatosis type 1, including multiple cafe au lait spots, several curaneous neurofibroma, and speckling of the irises. In addition, his unusual facial features consisted of telecanthus, antimongoloid slant of the palpebral fissures, a broad base of the nose, low set and mildly posteriorly rotated ears, thick helices, high arched palate, short and pointed chin, and low posterior hairline. We propose that deletions of the NF-1 gene and/or contiguous genes are the etiology of neurofibromatosis type 1 and unusual facial features. This particular facial appearance was inherited from the patient`s mother and has been described in other individuals with neurofibromatosis type 1. We are using FISH to rapidly screen patients with this phenotype for large deletions involving the NF-1 gene and flanking DNA sequences.

  14. Math Learning Disability and Math LD Subtypes: Evidence from Studies of Turner Syndrome, Fragile X Syndrome, and Neurofibromatosis Type 1.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.

    2001-01-01

    This study examined whether indicators of math learning disability were observed in 35 5- and 6-year-olds with either neurofibromatosis, Turner Syndrome, or fragile X syndrome and compared to controls. Findings indicate that girls with fragile X or Turner syndrome but not neurofibromatosis are significantly more likely to have specific math…

  15. Recurrent peptic ulcer disease in a pediatric patient with type 1 neurofibromatosis and primary ciliary dyskinesia.

    PubMed

    Lionetti, E; Francavilla, R; Ruggieri, M; Di Stefano, V; Principi, M B; Pavone, L

    2009-10-01

    Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder with characteristic features of skin and central nervous system involvement. Gastrointestinal complications are rare, especially during childhood. In adults, only two cases of peptic ulcer have been reported in neurofibromatosis, both due to Zollinger-Ellison syndrome. Peptic ulcer disease (PUD) may be primary or secondary in nature and it may be life threatening in the acute phase due to the risk of perforation. A case of recurrent gastrointestinal hemorrhage in a child with systemic neurofibromatosis and primary ciliary dyskinesia (PCD) is presented. The upper gastrointestinal endoscopy revealed the presence of multiple gastric ulcers. The ulcers scarred after the long-term administration of a proton pump inhibitor (PPI), but recurred after the suspension. Laboratory and imaging studies excluded Zollinger-Ellison syndrome and other known causes of PUD, suggesting a potential role of neurofibromatosis itself and primary ciliary dyskinesia in developing of recurrent PUD. As early diagnosis of PUD is vital for patient survival, this case report highlights the possible association of neurofibromatosis and PCD with this condition, responsive to PPI therapy and the potential need of gastric protection before complications arise.

  16. Cognitive profiles of neurofibromatosis type 1 patients with minor brain malformations.

    PubMed

    Acosta, Maria T; Walsh, Karin S; Kardel, Peter G; Kutteruf, Rachel E; Bhatt, Rujuta R; Bouton, Tara C; Vezina, Louis-Gilbert; Packer, Roger J

    2012-04-01

    Neurofibromatosis type 1 is a genetic condition associated with increased risk of abnormal brain development. The relationship between a specific type of brain malformation and a distinct cognitive sign/deficiency remains unknown. This study investigated the frequency of brain malformations in children with neurofibromatosis type 1, and the impact of those brain malformations on cognitive performance. A retrospective examination was performed of cranial magnetic resonance imaging and clinical records in 604 neurofibromatosis type 1 patients. Eighteen patients with brain malformations and intellectual evaluations were available and compared to a subset of neurofibromatosis type 1 patients (n = 20) without brain malformations. The most common brain malformations included hypothalamic hamartomas and Chiari I malformation. More complex migration disorders were also observed. Comparisons of cognitive profiles between groups revealed differences in patients with hamartomas compared with those manifesting Chiari I malformations or control subjects. As a group, those with hamartomas demonstrated below-average global intellect, whereas patients with Chiari I or no malformations performed in the average range. Disorders in cell organization, expressed as brain malformations (hamartomas or more complex defects), may comprise part of the expression of organizational and developmental defects in patients with neurofibromatosis type 1 and possibly other rat sarcoma gene-mitogen activated protein kinase pathway disorders.

  17. Life-threatening Duodenal Ulcer Bleeding from a Ruptured Gastroduodenal Artery Aneurysm in a Patient with Neurofibromatosis Type 1.

    PubMed

    Im, Kyu Sung; Kim, Sunyong; Lim, Jun Uk; Jeon, Jung Won; Shin, Hyun Phil; Cha, Jae Myung; Joo, Kwang Ro; Lee, Joung Il; Park, Jae Jun

    2015-09-01

    Vasculopathy is rarely reported in neurofibromatosis type 1, but when it occurs it primarily involves the aorta and its main branches. Among vasculopathies, aneurysmal dilatation is the most common form. Although several case reports concerning aneurysms or pseudoaneurysms of visceral arteries in neurofibromatosis type 1 patients have been reported, there are no reports describing gastroduodenal artery aneurysms associated with neurofibromatosis type 1. We experienced a case of life-threatening duodenal ulcer bleeding from a ruptured gastroduodenal artery aneurysm associated with neurofibromatosis type 1. We treated our patient by transarterial embolization after initial endoscopic hemostasis. To our knowledge, this is the first reported case of its type. High levels of suspicion and prompt diagnosis are required to select appropriate treatment options for patients with neurofibromatosis type 1 experiencing upper gastrointestinal bleeding. Embolization of the involved arteries should be considered an essential treatment over endoscopic hemostasis alone to achieve complete hemostasis and to prevent rebleeding.

  18. Regression of gadolinium-enhanced lesions in patients affected by neurofibromatosis type 1.

    PubMed

    Lucchetta, Marta; Manara, Renzo; Perilongo, Giorgio; Clementi, Maurizio; Trevisson, Eva

    2016-03-01

    Neurofibromatosis type I is a genetic condition with an autosomal dominant transmission characterized by neurocutaneous involvement and a predisposition to tumor development. Central nervous system manifestations include benign areas of dysmyelination and possibly hazardous glial tumors whose clinical management may result challenging. Here, we report on three patients diagnosed with Neurofibromatosis type I whose brain MRI follow-up showed the presence of gadolinium-enhancing lesions which spontaneously regressed. In none of the three cases, the lesions showed any clinical correlate and eventually presented a striking reduction in size while gadolinium enhancement disappeared despite no specific therapy administration during the follow-up. Although their nature remains undetermined, these lesions presented a benign evolution. However, they might be misdiagnosed as potentially life-threatening tumors. Hitherto, a similar behavior has been described only in scattered cases and we believe these findings may be of particular interest for the clinical management of patients affected by neurofibromatosis type I.

  19. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1

    PubMed Central

    Ferner, Rosalie E; Huson, Susan M; Thomas, Nick; Moss, Celia; Willshaw, Harry; Evans, D Gareth; Upadhyaya, Meena; Towers, Richard; Gleeson, Michael; Steiger, Christine; Kirby, Amanda

    2007-01-01

    Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications. PMID:17105749

  20. Precocious puberty associated with neurofibromatosis and optic gliomas. Treatment with luteinizing hormone releasing hormone analogue.

    PubMed

    Laue, L; Comite, F; Hench, K; Loriaux, D L; Cutler, G B; Pescovitz, O H

    1985-11-01

    Seven children with central precocious puberty and either neurofibromatosis and/or optic gliomas were referred to the National Institutes of Health, Bethesda, Md, for evaluation and treatment with the long-acting luteinizing hormone releasing hormone analogue (LHRHa) D-Trp6-Pro9-NEt-LHRH. Only six of the seven children chose to receive treatment. Four children presented with neurofibromatosis, three of whom also had optic gliomas; the remaining three children had isolated optic gliomas, without other neurocutaneous stigmas. All had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis. Six months of LHRHa therapy caused suppression of gonadotropin and sex steroid levels, stabilization or regression of secondary sexual characteristics, and decreases in growth velocity and the rate of bone age maturation. We conclude that LHRHa therapy is effective in the treatment of central precocious puberty secondary to neurofibromatosis and/or optic gliomas.

  1. Neurofibromatosis Type 1: Transcatheter Arterial Embolization for Ruptured Occipital Arterial Aneurysms

    SciTech Connect

    Kanematsu, Masayuki; Kato, Hiroki; Kondo, Hiroshi; Goshima, Satoshi; Tsuge, Yusuke; Kojima, Toshiaki; Watanabe, Haruo

    2011-02-15

    Two cases of ruptured aneurysms in the posterior cervical regions associated with type-1 neurofibromatosis treated by transcatheter embolization are reported. Patients presented with acute onset of swelling and pain in the affected areas. Emergently performed contrast-enhanced CT demonstrated aneurysms and large hematomas widespread in the posterior cervical regions. Angiography revealed aneurysms and extravasations of the occipital artery. Patients were successfully treated by percutaneous transcatheter arterial microcoil embolization. Transcatheter arterial embolization therapy was found to be an effective method for treating aneurysmal rupture in the posterior cervical regions occurring in association with type-1 neurofibromatosis. A literature review revealed that rupture of an occipital arterial aneurysm, in the setting of neurofibromatosis type 1, has not been reported previously.

  2. Neurofibromatosis Type 1 Presenting with Ophthalmic Features: A Case Series

    PubMed Central

    Jain, Gunjan; Sharma, Indra Kumar; Sharma, Reena; Saraswat, Neeraj

    2016-01-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder involving multiple systems and affects approximately 1 out of 3000 persons. Ocular manifestations are lisch nodules, plexiform neurofibroma, optic pathway gliomas. The proper diagnosis of NF-1 is a crucial task for a clinician due to the various clinical manifestations including vision and life threatening malignancies in few patients, which may arise in the different phases of life. The authors report three cases of NF-1, presenting with ophthalmic symptoms in teenager boys. On further ophthalmic and paediatric evaluation the diagnosis of NF-1 was confirmed on the basis of clinical criteria. This series also describe the abnormal facial features like telecanthus and broad nose which has been reported rarely. Case 1 was kept under regular follow-up and Case 2 and Case 3 were planned for the debulking surgery for plexiform neurofibroma of upper eye lid. A multidisciplinary approach is required to diagnose and treat such patients keeping in mind the myriad of clinical manifestations and life-long follow-up is required. PMID:28050470

  3. Genomic organization of the neurofibromatosis 1 gene (NF1)

    SciTech Connect

    Li, Y.; O`Connell, P.; Huntsman Breidenbach, H.

    1995-01-01

    Neurofibromatosis 1 maps to chromosome band 17q11.2, and the NF1 locus has been partially characterized. Even though the full-length NF1 cDNA has been sequenced, the complete genomic structure of the NF1 gene has not been elucidated. The 5{prime} end of NF1 is embedded in a CpG island containing a NotI restriction site, and the remainder of the gene lies in the adjacent 350-kb NotI fragment. In our efforts to develop a comprehensive screen for NF1 mutations, we have isolated genomic DNA clones that together harbor the entire NF1 cDNA sequence. We have identified all intron-exon boundaries of the coding region and established that it is composed of 59 exons. Furthermore, we have defined the 3{prime}-untranslated region (3{prime}-UTR) of the NF1 gene; it spans approximately 3.5 kb of genomic DNA sequence and is continuous with the stop codon. Oligonucleotide primer pairs synthesized from exon-flanking DNA sequences were used in the polymerase chain reaction with cloned, chromosome 17-specific genomic DNA as template to amplify NF1 exons 1 through 27b and the exon containing the 3{prime}-UTR separately. This information should be useful for implementing a comprehensive NF1 mutation screen using genomic DNA as template. 41 refs., 3 figs., 2 tabs.

  4. Identification of the neurofibromatosis type 1 gene product

    SciTech Connect

    Gutmann, D.H.; Wood, D.L.; Collins, F.S. )

    1991-11-01

    The gene for neurofibromatosis type 1 (NF1) was recently identified by positional cloning. The complete cDNA encodes a polypeptide of 2818 amino acids. To study the NF1 gene product, antibodies were raised against both fusion proteins and synthetic peptides. Initial characterization of two anti-peptide antibodies and one fusion-protein antibody demonstrated a specific protein of {approx}250 kDa by both immunoprecipitation and immunoblotting. This protein was found in all tissues and cell lines examined and is detected in human, rat, and mouse tissues. To demonstrate that these antibodies specifically recognize the NF1 protein, additional fusion proteins containing the sequence specific to the synthetic peptide were generated. Both peptide antisera recognize the proper specific fusion proteins so generated. Immunoprecipitates using the peptide antisera were shown to recognize the same protein detected by immunoblotting with either the other peptide antiserum or the fusion-protein antiserum. Immunoblotting using antiserum specific to spatially distinct epitopes conducted on tissue homogenates demonstrated the NF1 protein in all adult tissues. Based on the homology between the NF1 gene product and members of the GTPase-activating protein (GAP) superfamily, the name NF1-GAP-related protein (NF1GRP) is suggested.

  5. Phenotypic variability in monozygotic twins with neurofibromatosis 2

    SciTech Connect

    Baser, M.E.; Ragge, N.K.; Riccardi, V.M.

    1996-09-06

    Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affected organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes. 42 refs., 1 tab.

  6. Blepharoplasty techniques in the management of orbito-temporal neurofibromatosis.

    PubMed

    Li, Jin; Lin, Ming; Shao, Chunyi; Ge, Shengfang; Fan, Xianqun

    2014-11-01

    We aimed to present blepharoplasty techniques we used for severe orbito-temporal neurofibromatosis (NF). A retrospective noncomparative single-center case study was undertaken on patients with orbito-temporal NF. Twenty-two patients with orbito-temporal NF treated at the Department of Ophthalmology of Shanghai Ninth People's Hospital between 2007 and 2011 participated in the study. They underwent a standard ophthalmologic assessment for orbito-temporal NF involving both the orbito-temporal soft tissue and bony orbits. The orbits were examined with three-dimensional computed tomography (CT) and all 22 patients underwent tumor debulking, blepharoplasty, and orbital reconstruction. We modified the conventional procedures. Our reconstructive techniques included eyelid reduction; lateral canthal reattachment; for patients with collapse of the lateral orbital margin, reconstruction of the orbital margin to be performed before reattaching the lateral canthus to the implanted titanium mesh; anterior levator resection; and frontalis suspension according to preoperative levator muscle function. Visual acuity, tumor recurrence, and postoperative palpebral fissure and orbital appearance were evaluated to assess outcomes. Acceptable cosmetic results were obtained in 22 patients after debulking of the orbito-temporal NF and surgical reconstruction. There was no loss of vision or visual impairment postoperatively. All patients did not display recrudescence after a follow-up period of >1 year. Three patients with residual ptosis were successfully treated with a second ptosis repair. We believe that the blepharoplasty techniques described in the treatment of orbito-palpebral NF may provide both functional and esthetic benefits.

  7. Clinical application of digital indocyanine green angiography in choroidal neurofibromatosis.

    PubMed

    Rescaldani, C; Nicolini, P; Fatigati, G; Bottoni, F G

    1998-01-01

    Indocyanine green angiography (ICGA) was used to investigate 2 cases of type 1 systemic neurofibromatosis that had appeared at birth with café-au-lait skin spots, gradually developing into multiple cutaneous neurofibromas. Patients underwent periodical visual acuity examinations, the fundus was checked and fluorescein angiography (FA) was done; all findings appeared extremely stable. In 1995 these 2 patients underwent ICGA to check for pathological choroidal involvement. In both cases the initial examination stages showed multiple extensive areas of hypofluorescence, their morphology and extension coinciding with the retinal pigment epithelium (RPE) lesions shown by FA and by ophthalmoscopic examination. In later stages the hypofluorescent areas became smaller, generally shrinking to small isolated dots in the middle of the original areas. These initially hypofluorescent areas appeared to be due to slow focal choroidal filling caused by deep alterations to the walls of the choroidal arterioles induced by the disease. Chronic hypoperfusion of the choriocapillaris results in impairment of the overlying RPE, causing it to atrophy. The late hypofluorescent areas could be either persistent nonperfused lobules of choriocapillaris or neurofibromatose choroidal nodules. ICGA examination showed that the FA lesions described in the literature as choroidal nodules are in fact alterations to the RPE secondary to areas of hypoperfusion in the choriocapillaris.

  8. Vertebral scalloping in neurofibromatosis type 1: a quantitative approach

    PubMed Central

    Kwok, Edmund S.H.; Sawatzky, Bonita; Birch, Patricia; Friedman, Jan M.; Tredwell, Stephen J.

    2002-01-01

    Objective To investigate quantitative differences in vertebral scalloping between children who have scoliosis with and without neurofibromatosis type 1 (NF1). Design A retrospective study. Setting A university-affiliated children’s hospital. Patients Twenty-seven children with scoliosis, 13 of whom had NF1 and 14 of whom did not. Method Existing radiographs of the lumbar vertebrae were used to measure and compare the degree of vertebral scalloping. Main outcome measures The distribution of posterior scalloping ratios in the 2 groups and the most extreme ratio in each subject in each group were compared. Results Scalloping ratios from the children with NF1 were not normally distributed: 31% had ratios greater than 1.20. Scalloping ratios from the non-NF1 children were normally distributed, with a mean ratio (and standard deviation) of 1.13 (0.03). The distribution between the 2 groups was significantly different (p < 0.05). Conclusions In children who have scoliosis but no NF1 there was a range of mild scalloping whereas those with NF1 has severe scalloping. Further studies are needed to determine the possible role of vertebral scalloping in scoliosis severity and progression in children who have NF1. PMID:12067169

  9. Neurofibromatosis type 2/Merlin: sharpening the myth of prometheus.

    PubMed

    Drvarov, Oliver; Cubero, Francisco Javier

    2011-05-01

    The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (NF2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma,suggesting that Nf2-/-progenitors can be a cell of origin for these tumors. Despite the suggested link between NF2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors,and that the overproliferation of Nf2-/-liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2-/-liver progenitors in vitro and in vivo, consistent with recent studies indicating that the NF2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together,our findings uncover a critical role for NF2/Merlin in controlling homeostasis of the liver stem cell niche.

  10. Complex Vertebral Arteriovenous Fistula and Ruptured Aneurysm in Neurofibromatosis

    PubMed Central

    Roth, Tori C.; Manness, Wayne K; Hershey, Beverly L.; Yazdi, Joseph

    2000-01-01

    The objective and importance of this study was to describe the challenges encountered with treating a high-flow vertebral arteriovenous fistula (AVF) and ruptured aneurysm in a patient with life-threatening hemorrhage. A 36-year-old female with Neurofibromatosis type 1 (NF1) presented 2 weeks after uneventful cesarean section with a rapidly expanding pulsatile neck mass. Angiography demonstrated a complex left vertebral AVF and multiple associated vertebral artery aneurysms. Emergent endovascular coil embolization was performed using a retrograde and antegrade approach to occlude the fistulas and trap the ruptured aneurysm, successfully treating the acute hemorrhage. Subsequent definitive therapy was accomplished utilizing a combined neurointerventional and neurosurgical strategy of direct-puncture acrylic embolization and ligation of the vertebral artery. Recent advances in neurointerventional technology allow novel approaches in the primary and/or preoperative treatment of complex vascular lesions such as those seen in NF1. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5p40-b PMID:17171099

  11. Neurofibromatosis: relinquishing the masks; a quest for quality of life.

    PubMed

    Messner, R; Smith, M N

    1986-07-01

    Neurofibromatosis (NF) or von Recklinghausen's disease is mankind's most common neurologic genetic disorder, occurring in one of every 3000 live births. While many individuals with NF suffer disfiguring, disabling, or life-threatening complications, NF is extremely variable in its symptoms, intensity, and progression. For many of its victims, NF is a pseudonym for uncertainty and physical and psychosocial havoc. John Merrick, 'The Elephant Man', endured one of the most severe cases of NF ever recorded. Merrick's rejection by post-Dickensian England forced him to become a sideshow circus attraction just to survive. The essence of nursing intervention with NF patients and their families engaged in the quest for quality of life is to restore them to optimal physical and psychosocial functioning, and, ideally, to help them utilize the experience for growth. Many individuals respond to the frustration of NF and society's reactions to the disorder by the wearing of psychological masks. Likewise, nurses may wear emotional masks as a defence against their own discomfort and fears concerning the disorders. Comprehensive nursing management of NF is realized only as nurses and patients relinquish their respective masks. This article examines the nurse's role in genetic disorders with special considerations presented by NF. Adaptation to NF involves coping with NF and its accompanying sequelae and coping with life as it is affected by NF. The concepts of 'chromosomal coping', 'genetophobia', 'genetic guilt, and 'genetic overload syndrome' are presented and analyzed utilizing the theoretical nursing frameworks of Imogene King and Sister Callista Roy.

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

    PubMed Central

    Orraca-Castillo, Miladys; Estévez-Pérez, Nancy; Reigosa-Crespo, Vivian

    2014-01-01

    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. PMID:24936179

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

    PubMed Central

    Bender, Luciano Pereira; Meyer, Maria Rita F.; Rosa, Rafael Fabiano M.; Rosa, Rosana Cardoso M.; Trevisan, Patrícia; Zen, Paulo Ricardo G.

    2013-01-01

    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. PMID:24473962

  14. [Social representations of patients and relatives regarding Type 1 Neurofibromatosis].

    PubMed

    Cerello, Alessandra Craig; Gianordoli-Nascimento, Ingrid Faria; Moreira, Alline Hellen; Rocha, Virgínia Silva; Ribeiro, Luciana de Moura; de Rezende, Nilton Alves

    2013-08-01

    Type 1 Neurofibromatosis (NF1) is a disease with diverse manifestations. Few studies have addressed the psychological aspects associated with it from the perspective of those who have NF1 or their relatives. In this study 46 subjects were interviewed, 28 people with NF1 (Group P) and 18 relatives (Group F) seeking to identify the understanding of the day-to-day reality experienced by these two groups and possible distinctions between them, based on the social representations of each group. Data analysis was conducted using Classic Content Analysis. The respondents' answers were organized into categories and subcategories based on their meanings. The results revealed that the quantitative distribution of the categories had similar frequencies for both groups. However, important qualitative differences were observed in terms of the meanings of the answers. Difficulty in obtaining information about NF1 along with few references about social support networks by people with the disease or their family members contributed to the identification of a veil of social invisibility around NF1. These aspects highlight the need for greater investment in research and intervention related to NF1 in order to expand the social coping conditions for those afflicted with the disease.

  15. Effects of neurofibromatosis type 1 on children's development.

    PubMed

    Haynes, Norris M; Kirwan, Jacqueline R; McCrohan, Kelly

    2011-01-01

    In-depth study of the human genome holds the potential to provide needed focus on genetic disorders that affect hundreds of thousands of children and significantly affect their development. Neurofibromatosis Type-1 (NF-1) is one of the most common genetic disorders that affect neurological, cognitive, social, and physical development. NF-1 affects all racial groups and both genders equally. NF-1 occurs in about 1 in 2,500 to 3,300 individuals in the population. The incidence rate at birth is about 0.0004 births in the United States and is growing in prevalence. Children with NF-1 experience a range of psychomotor and cognitive impairments that affect the quality of their social lives and their learning and academic achievements. Interventions to address the psychosocial and educational needs of children with NF-1 include a range of social and academic support services, which are most effective when they are comprehensive, involve a multidisciplinary team of educational and health experts, and include a focus on supporting and empowering family members to be effective caregivers. Efforts to address the needs of children with NF-1 and to provide adequate support to their families have significant policy implications for local, state, and federal officials.

  16. Neurosurgical implications of neurofibromatosis Type I in children.

    PubMed

    Al-Otibi, Merdas; Rutka, James T

    2006-01-15

    Neurofibromatosis Type 1 (NF1) is one of the most common inherited diseases in humans. It is caused by a mutation in the NF1 gene on chromosome 17, and is associated with numerous central and peripheral nervous system manifestations. Children with NF1 are at high risk of harboring numerous lesions that may require the attention of a neurosurgeon. Some of these include optic nerve gliomas, hydrocephalus, intraspinal tumors, and peripheral nerve tumors. Although most of the neoplasms that affect the brain, spine, and peripheral nerves of children are low-grade lesions, there is a small but real risk that some of these lesions may become high grade over time, requiring other forms of therapy than surgery alone. Other associated disorders that may result from NF1 in childhood include Chiari malformation Type I, scoliosis, and pulsating exophthalmos from the absence of the sphenoid wing. In this review, the major lesions that are found in children with NF1 are reviewed as well as the types of treatment that are offered by neurosurgeons and other members of the treating team. Today, optimum care of the child with NF1 is provided by a multidisciplinary team comprising neurosurgeons, neurologists, ophthalmologists, radiologists, orthopedic surgeons, and plastic surgeons.

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

    PubMed

    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.

  18. Deficient motor timing in children with neurofibromatosis type 1.

    PubMed

    Debrabant, Julie; Plasschaert, Ellen; Caeyenberghs, Karen; Vingerhoets, Guy; Legius, Eric; Janssens, Sandra; Van Waelvelde, Hilde

    2014-11-01

    Neurofibromatosis type 1 (NF1) is one of the most common single-gene disorders affecting fine and visual-motor skills. This case-control study investigated motor timing as a possible related performance deficit in children with NF1. A visual-motor reaction time (VRT) test was administered in 20 NF1 children (mean age 9 years 7 months) and 20 age- and gender-matched typically developing (TD) children. Copying and tracing performance were evaluated using the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI). Children with NF1 responded with an increased reaction time (RT) to temporally predictive stimuli compared to TD children, whereas RT at unpredictive stimuli did not differ between groups. Motor timing indexed by the RT decrease at predictive stimuli significantly associated with the Beery VMI copy and tracing outcomes. Deficient motor timing as an actual symptom may add to further research on the pathogenesis of NF1-associated motor impairment and the development of more effective treatment.

  19. Somatic mosaicism in a patient with neurofibromatosis type 1.

    PubMed Central

    Colman, S. D.; Rasmussen, S. A.; Ho, V. T.; Abernathy, C. R.; Wallace, M. R.

    1996-01-01

    Using loss of heterozygosity analysis, a method designed to detect moderate to large gene deletions, we have identified a new-mutation neurofibromatosis type 1 (NF1) patient who is somatically mosaic for a large maternally derived deletion in the NF1 gene region. The deletion extends at least from exon 4 near the 5' end of the gene to intron 39 near the 3' end. The gene-coding region is, therefore, mostly or entirely deleted, encompassing a loss of > or = 100 kb. We hypothesize that the deletion occurred at a relatively early developmental timepoint, since signs of NF1 in this patient are not confined to a specific body region, as seen in "segmental" NF, and since both mesodermally and ectodermally derived cells are affected. This report provides the first molecular evidence of somatic mosaicism in NF1 and, taken together with a recent report of germ-line mosaicism in NF1, adds credence to the concept that mosaicism plays an important role in phenotypic and genetic aspects of NF1 and may even be a relatively common phenomenon. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8644707

  20. [Voluminous plexiform neurofibromas of the neck region in neurofibromatosis 1].

    PubMed

    Pascual-Castroviejo, Ignacio; Pascual-Pascual, Samuel I; Velazquez-Fragua, Ramón; Viaño, Juan; Quiñones-Tapia, Diana; López-Barea, Fernando

    2014-07-01

    AIM. To present the clinic, imaging and evolutive characteristics of a series of patients with neurofibromatosis 1 with voluminous plexiform neurofibromas in the neck (VPNFN) during childhood. PATIENTS AND METHODS. Nine patients (five females and four males) who were diagnosed as VPNFN at ages between 3 and 15 years. The VPNFN widespread to the posterior fossa or the upper thoracic region in some cases. The diagnosis was based on the clinical, imaging and histological findings. RESULTS. One of the tumors was intralaryngeal and caused respiratory difficulties. The other eight patients had the origin of the tumor in several spinal roots of one or both sides and could growth to the posterior fossa and to the upper thoracic region in some cases with displacement of the surrounding organs, especially in three patients, all girls, in whom the tumor reached a voluminous size on one side, that was observed only until 10 to 11 years when the growth ceased. CONCLUSIONS. The VPNFN are histologically benign tumors. Those located in the larynx must be removed because of the respiratory problems, but it is not necessary in cases with other locations despite the voluminous size that can reach in some patients with great displacement of the surrounding organs. The analysis of the results of our series may demonstrate that al least the extralaryngeal tumors only grow to 11-12 years of age. This possibility may make recommendable to retard the surgical treatment as much as possible in cases that it is not necessary.

  1. Neurofibromatosis and lessons for the war on cancer.

    PubMed

    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.

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

    PubMed

    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.

  3. Absence of a sphenoid wing in neurofibromatosis type 1 disease: imaging with multidetector computed tomography.

    PubMed

    Onbas, Omer; Aliagaoglu, Cihangir; Calikoglu, Cagatay; Kantarci, Mecit; Atasoy, Mustafa; Alper, Fatih

    2006-01-01

    Neurofibromatosis type 1 disease is characterized by pigmented cutaneous lesions and generalized tumors of a neural crest origin and it may affect all the systems of the human body. Sphenoid dysplasia is one of the characteristics of this syndrome and it occurs in 5-10% of the cases; further, abnormalities of the sphenoid wings are often considered pathognomonic. However, complete agenesis of a sphenoid wing is very rare. We report here on an unusual case of neurofibromatosis type 1 disease with the associated absence of a sphenoid wing that was diagnosed by using multidetector computed tomography.

  4. Bilateral Mirror Image Cervical Neurofibroma in an Adult with Neurofibromatosis Type 1

    PubMed Central

    Pandey, Sharad; Singh, Kulwant; Sharma, Vivek; Khan, Mohammed Tabish; Ghosh, Amrita; Santhosh, Deepa

    2017-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterised by various phenotypic features like hyperpigmented spots, neurofibromas, Lisch nodules, skeletal abnormalities and tendency to develop neoplasms. Only few cases of Non-Familial Spinal Neurofibromatosis-1 (Non-FSNF1) have been described in literature with tumors involving the spinal roots at every level being even rarer. We reported an interesting case of bilateral symmetrical cervical neurofibroma with multiple spinal neurofibromas appearing as mirror image on CT, associated with non familial NF-1 as a rare presentation in a 25-year-old adult male.

  5. Research update and recent developments in the management of scoliosis in neurofibromatosis type 1.

    PubMed

    Wang, Zhenyu; Liu, Yi

    2010-05-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominant hereditary disease characterized by an abnormal proliferation of cells from the neural crest. Neurofibromatosis type 1 is often associated with orthopedic disorders, especially scoliosis, which is the most common skeletal manifestation of NF-1. The effects of treatment of scoliosis in NF-1 are less satisfactory than other scoliotic types due to the particular pathogenesis and clinical characteristics. Early diagnosis and treatment may be the best way to improve outcomes. This article summarizes the recent genetic and clinical developments of scoliosis in NF-1.

  6. Planning deficit in children with neurofibromatosis type 1: a neurocognitive trait independent from attention-deficit hyperactivity disorder (ADHD)?

    PubMed

    Galasso, Cinzia; Lo-Castro, Adriana; Di Carlo, Loredana; Pitzianti, Maria Bernarda; D'Agati, Elisa; Curatolo, Paolo; Pasini, Augusto

    2014-10-01

    Neurofibromatosis type 1 is associated with executive dysfunctions and comorbidity with attention-deficit hyperactivity disorder (ADHD) in 30% to 50% of children. This study was designed to clarify the neurocognitive phenotype observed in neurofibromatosis type 1 by testing the hypothesis that children with neurofibromatosis type 1 have specific planning deficits independently from intellectual level and ADHD comorbidity. Eighteen children with neurofibromatosis type 1 were pair-matched to 18 children with ADHD and 18 healthy controls. All groups were assessed on the presence of ADHD symptoms (Conners Scales) and planning deficits (Tower of London). Compared with control group, groups with neurofibromatosis type 1 and ADHD demonstrated significant impairment of planning and problem solving. The lack of correlation between Tower of London results and Conners subscale scores in neurofibromatosis type 1 group confirmed that the planning and problem-solving deficit is not directly related to inattention level. These findings suggested that the executive impairment probably represents a peculiar trait of neurofibromatosis type 1 neurocognitive phenotype.

  7. A rare case of segmental neurofibromatosis with multiple blue-red pseudoatrophic plaques.

    PubMed

    Diociaiuti, Andrea; Guidi, Beatrice; Surrenti, Tiziana; Boldrini, Renata; Callea, Francesco; El Hachem, May

    2014-09-01

    We report the case of a 5-year-old girl who presented with 2 blue-red atrophic plaques on the left leg as well as subcutaneous nodules that were present since infancy. Although the clinical criteria of neurofibromatosis (NF) were absent, microscopic examination revealed features of a blue-red neurofibroma.

  8. Ruptured Aneurysm of Intercostal Arteriovenous Malformation Associated With Neurofibromatosis Type 1: A Case Report

    SciTech Connect

    Kim, Hyung Jun; Seon, Hyun Ju Choi, Song; Jang, Nam Kyu

    2011-02-15

    Intercostal arteriovenous malformations (AVM) are rare, with most being secondary to trauma or iatrogenic therapeutic procedures. Only one case of presumably congenital AVM has been reported. Here we report the first case of a ruptured aneurysm of intercostal AVM associated with neurofibromatosis type 1 in a 32-year-old woman who experienced hypovolemic shock caused by massive hemothorax.

  9. Spontaneous Massive Hemothorax in a Patient with Neurofibromatosis Type 1 with Successful Transarterial Embolization

    PubMed Central

    Rookkapan, Sorracha; Tanutit, Pramot; Pakdeejit, Songklod; Songjamrat, Apiradee; Sungsiri, Jitpreedee

    2013-01-01

    Vascular involvement in neurofibromatosis type 1 is rare but has the potential to be fatal. We report a case of a patient with spontaneous rupture of a left intercostal artery aneurysm, which presented as a massive left hemothorax and was successfully treated by transarterial coil embolization. PMID:23323035

  10. Behavioural, Academic and Neuropsychological Profile of Normally Gifted Neurofibromatosis Type 1 Children

    ERIC Educational Resources Information Center

    Descheemaeker, M.-J.; Ghesquiere, P.; Symons, H.; Fryns, J. P.; Legius, E.

    2005-01-01

    In the present study the neuropsychological, academic and social-emotional profiles were examined in Neurofibromatosis type 1 (NF1) children. Subjects: 17 NF1 children (ages 7-11) with NF1 without serious medical problems and with a full scale IQ (FSIQ) above 70. Wechsler Intelligence Scale for Children-Revised (WISC-R), academic tests and an…

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

    ERIC Educational Resources Information Center

    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…

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

    ERIC Educational Resources Information Center

    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…

  13. Autopsy case of concurrent Huntington's disease and neurofibromatosis type 1.

    PubMed

    Kawakami, Ito; Katsuse, Omi; Aoki, Naoya; Togo, Takashi; Suzuki, Kyoko; Isojima, Daisuke; Kondo, Daizo; Iseki, Eizo; Kosaka, Kenji; Akiyama, Haruhiko; Hirayasu, Yoshio

    2014-03-01

    We report here an autopsy case of concurrent Huntington's disease (HD) and neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. The patient was a Japanese woman with a significant hereditary burden: seven of her family members within four generations were affected by either NF1 or concurrent HD and NF1. She was diagnosed as having NF1 at age 24. At age 40, she showed signs of irritability, aggressive and childish behaviour, which became progressively worse. At age 48, rigidity and spastic gait were observed. One year later, choreoathetoid involuntary movements became apparent. Diagnosis of HD was made by identification of the abnormally expanded cytosine-adenine-guanine repeats in the Huntington's disease gene. Her condition deteriorated gradually to an apallic state and she died at age 60. Post-mortem examination revealed extensive brain atrophy, which was particularly severe in the frontal and temporal cortices and the striatum. The degree of neurodegenerative change seemed to correspond to grade IV. Polyglutamine positive inclusions were seen frequently in all layers of the cerebral cortex and in the amygdala and hippocampus. Inclusions were also present in the striatum, but there were fewer than in the cortex. Remarkably, neuronal intranuclear inclusions were present in the cerebellum, although they are usually not seen in HD. Features associated with the central nervous system involvement of NF1 were not found in the brain, but HD pathology might have been accelerated by the concurrence of NF1. This is the third report of a case with concurrent HD and NF1 in the world, and the first study in which occurrence of polyglutamine inclusions was confirmed on post-mortem examination.

  14. PCR-based polymorphisms in neurofibromatosis type 1 (NFI)

    SciTech Connect

    Lai, P.S.; Chee, S.; Low, P.S.

    1994-09-01

    Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in humans with an incidence of 1 in 3,000. The NF1 gene is located on chromosome 17q 11.2 and encodes an ubiquitously expressed transcript of about 13kb. Direct mutation detection is difficult in this disorder due to the large gene size, high mutation rate and variety of mutations. We have studied the allele frequencies of seven PCR-based polymorphisms. Six of the probes used flank the NF1 gene, namely p11.3C4.2/Msp I (proximal), pEW206/Msp I (distal), p2.f9.8/Rsa I (distal), pEW207/Bgl II (distal), pEW207/Hind III (distal) and pHHH202/Rsa I (proximal). An intragenic RFLP, pEvi 2B-B/Eco R1 polymorphism in intron 27, was also analyzed by PCR. Allele frequencies for 48 normal unrelated individuals were obtained as follows: A1 = 0.40, A2 = 0.6 (p11.3C4.2/Msp I), A1 = 0.44, A2 = 0.56 (pEW206/Msp I), A1 = 0.17, A2 = 0.83 (p2.F9.8/Rsa I), A1 = 0.64, A2 = 0.36 (pEW207/Bgl I), A1 = 0.45, A2 = 0.55 (pEvi 2B-B/Eco RI). Heterozygosity rates of the alleles ranged from 20.8% to 51.7%. Using a combination of these markers, seven local families with NF1 were studied. Normal Mendelian segregation of alleles was observed in these families and no recombination was detected so far. These PCR-based markers were found to be useful for linkage analysis in our families.

  15. [Neurofibromatosis--an inborn genetic disorder with susceptibility to neoplasia].

    PubMed

    Karwacki, Marek W; Woźniak, Wojciech

    2006-01-01

    Among different subtypes of neurofibromatosis (Nf), type 1 (Nf-1) predominates in frequency (approximately 97% of Nfs' patients) with an incidence of approximately 1 in 3500 live births. Nf-2, comprises 2% of the Nf population and is a very rare disease (1:40,000). Both are autosomal dominant disorders with 100% penetration, variable expression and 50% rate of new (de novo) mutations. The protein products of both, NF1 andNF2 genes are best known and the genes serve as tumour suppressors. Mutations result in a predisposition to develop a variety of tumours of the central and peripheral nervous systems, as well as other malignancies. Nf-2 is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts with a paucity of cutaneous features, which are seen more consistently in Nf-1. In contrast to Nf-1, Nf-2 is associated with significant morbidity and decreased life span and a higher incidence of CNS tumours. However, morbidity and mortality rates in Nf-1 are not negligible. The cardinal features of Nf-1 are cafe-au-lait spots, axillary and inguinal freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). Optic gliomas and both malignant and benign peripheral nerve sheet tumours are the most common malignancies arising in Nf-1 patients. Among neurological symptoms epilepsy, intellectual disability and learning difficulty are also observed. Bone dysplasia results in scoliosis. There is no known medical treatment beneficial to both groups of patients. The mainstay of care for Nf patients is anticipatory guidance, and early detection and symptomatic treatment of disease complications.

  16. Bevacizumab for Treatment-Refractory Pain Control in Neurofibromatosis Patients

    PubMed Central

    Recht, Lawrence D

    2016-01-01

    Objective: Chronic pain is a well-known morbidity associated with neurofibromatosis (NF) for which better therapies are needed. Surgery, radiation, and pain medications have been utilized, but often fail to relieve debilitating pain. One patient at our institution was noted to have near complete resolution of pain after treatment with bevacizumab for progressive neurologic deficit associated with NF2, suggesting its potential as an effective pain control method. We aim to better characterize the use of bevacizumab for pain control in this subset of patients.  Patients and Methods: We retrospectively reviewed 38 NF patients treated at our institution.   Results: Of the 38 total NF patients, we found that 63% reported chronic pain, with 18% reporting chronic opiate usage. Nine patients with chronic pain were considered for bevacizumab treatment and five went on to receive infusions. Of these patients, four out of five had previous surgical debulking and two out of five had previous radiation for attempted pain control. One patient had a lesion not amenable to surgery or radiation. Patients received a median of 13 cycles of bevacizumab, and four out of five patients reported a decrease in subjective pain. All patients that had pain relief had a relapse of pain symptoms when the dose was reduced or infusions were paused. Seventy-five percent were able to decrease opiate use. No major complications were noted. All five patients have elected to continue infusions for pain control.  Conclusion: Bevacizumab was, in general, well tolerated and should be considered as a treatment option in NF patients with chronic pain refractory or not amenable to surgical decompression and debulking, radiation, and pain medication.   PMID:28123914

  17. Criptococosis cutánea primaria en paciente inmunocompetente.

    PubMed

    Vázquez-Osorio, Igor; García-Rodiño, Sara; Rodríguez-Rodríguez, Marta; Labandeira, Javier; Suárez-Peñaranda, José Manuel; Sánchez-Aguilar, MDolores; Vázquez-Veiga, Hugo

    2016-05-15

    La criptococosis cutánea es una micosis propia de pacientes inmunodeprimidos, sobre todo aquellos con infección por el virusde la inmunodeficiencia humana (VIH). Sin embargo, existen casos infrecuentes de criptococosis cutánea en pacientes inmunocompetentes, que suelen simular otras dermatosis, lo que retrasa su diagnóstico y tratamiento. Presentamos el caso de un varón pluripatológico de 79 años, con úlceras dolorosas en dorso de mano derecha que no respondían a tratamientos tópicos. A través del estudio histopatológico y micológico se alcanzó el diagnóstico de criptococosis cutánea primaria, lográndose la remisión de las lesiones tras 6 meses de tratamiento con fluconazol.

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

    PubMed

    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.

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

    DTIC Science & Technology

    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

  20. Congenital giant plexiform neurofibroma with occipital calvarial dysplasia in association with meningoencephalocele in neurofibromatosis Type 1 and segmental neurofibromatosis: report of 2 cases.

    PubMed

    Dadlani, Ravi; Sadanand, Venkatraman; Ghosal, Nandita; Hegde, Alangar S

    2013-11-01

    Giant plexiform neurofibroma (GPNF) of the scalp is an extremely rare lesion reported in association with neurofibromatosis. Occipital location of GPNF is even more infrequent, especially in association with occipital dysplasia (OD). The authors report 2 pediatric cases of GPNF associated with OD. The first case had an associated meningoencephalocele, and the second had large vascular channels within the lesion and the dominant ipsilateral transverse sinus lying in the center of the calvarial defect. The authors present these 2 unusual cases with a review of literature and discuss the radiological findings, theories of etiopathogenesis of the OD, and management dilemmas.

  1. Localized neurofibromatosis of the female genital system: a case report and review of the literature.

    PubMed

    Gómez-Laencina, Ana M; Martínez Díaz, Francisco; Izquierdo Sanjuanes, Blanca; Vicente Sánchez, Elena M; Fernandez Salmerón, Rosario; Meseguer Peña, Francisco

    2012-06-01

    Neurofibromatosis within the female genital tract is uncommon. The vulva is the most frequent genital location, but it has rarely been reported in the context of the vagina, uterine cervix or ovaries. In spite of its rarity, neurofibroma is a neoplasm that should be considered in the differential diagnosis of pelvic masses, especially in patients with neurofibromatosis. In this paper we describe the case of a 71-year-old patient with pelvic pain and a uterine mass who underwent a hysterectomy after having been diagnosed with an 11-cm neurofibroma occupying the myometrium of the entire uterine corpus. There were no neurofibromas in the endometrium, serosa, fallopian tubes or ovaries. The patient had an unknown von Recklinghausen's disease.

  2. Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.

    PubMed

    Vurallı, Doğuş; Gönç, Nazlı; Vidaud, Dominique; Özön, Alev; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

    2016-03-05

    Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD.

  3. Voltage-Gated ion currents of schwann cells in cell culture models of human neurofibromatosis.

    PubMed

    Fieber, Lynne A

    2003-11-01

    K(+) (K) channels play a role in the proliferation of many cell types in normal cells and certain disease states. Several laboratories have studied K currents in cultured Schwann cells from models of the human diseases, neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). These diseases are characterized by the growth of Schwann cell tumors. In all cell culture NF models the K current properties differ in tumor-derived and normal Schwann cells. Depending on the model however, the type of K channel abnormality differs. K channels appear to play a role in the proliferation of Schwann cell cultures of these disease models, because a link has been established between K current blockade and the inhibition of Schwann cell proliferation in NF1 and NF2. Differences in the proliferation response of normal Schwann cells to K channel blockers suggest that in vitro regulation of proliferation in neoplastic and normal Schwann cells is complex.

  4. Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome

    PubMed Central

    Vurallı, Doğuş; Gönç, Nazlı; Vidaud, Dominique; Özön, Alev; Alikaşifoğlu, Ayfer; Kandemir, Nurgün

    2016-01-01

    Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD. PMID:26758488

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

    PubMed

    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.

  6. Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1: A Multicenter Project With 3 Clinical Trials

    DTIC Science & Technology

    2006-06-01

    Tumors in Neurofibromatosis Type 1: A Multicenter Project with 3 Clinical Trials PRINCIPAL INVESTIGATOR: David Viskochil, M.D., Ph.D...Trials 5b. GRANT NUMBER W81XWH-04-1-0502 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David Viskochil, M.D., Ph.D. 5d. PROJECT...submission of a clinical trial for neoadjuvant chemotherapy in MPNST (DAMD-NF043129; PI- David Viskochil). This proposal was not funded, however it was

  7. Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis

    DTIC Science & Technology

    2013-08-01

    Neurofibromatosis 1 and Scoliosis PRINCIPAL INVESTIGATOR: David W. Polly, Jr., MD CONTRACTING ORGANIZATION: UNIVERSITY OF MINNESOTA Minneapolis, MN 55455... David . W. Polly Jr., MD 5d. PROJECT NUMBER Christopher L. Moertel, MD Charles G.T. Ledonio, MD 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING...Characteristics AUTHORS (LAST NAME, FIRST NAME): Ledonio, Charles Gerald T.1; Polly, David W.1; Brearley, Ann M.1; Crawford, Alvin H.2; Sucato, Daniel J.3

  8. Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis Type I and Scoliosis

    DTIC Science & Technology

    2011-08-01

    Scoliosis: a prospective epidemiological study. J Bone Joint Surg Am 57:968-972. 3. Cummings RJ, Loveless EA, Campbell J, Samelson S, Mazur JM...J Bone Joint Surg Am. 1998 Aug;80(8):1107-11. 4. Crawford AH, Herrera-Soto J. Scoliosis associated with neurofibromatosis. Orthop Clin North Am...idiopathic scoliosis. J Bone Joint Surg Am. 1998 Aug;80(8):1097-106. 16. National Institute of Health Consensus Development Conference. NF-1. 1988. p

  9. An Unusual Case of Multiple Intraoral Manifestations of Neurofibromatosis Type 1: Case Report with Literature Review

    PubMed Central

    M, Sheejith; Joseph, Benny; Sheejith, Bhavya

    2014-01-01

    The various oral manifestations of neurofibromatosis in dentulous patients have been documented in literature. Although most of the previous documents have discussed on common findings like a prominent lingual papillae, or solitary overgrowth of gingival soft tissue, this article focuses on a relatively rare occurrence of multiple nodular manifestations of Neurofibromatosis–1 on an edentulous alveolar ridge, tongue, palate and lips of an elderly female patient. PMID:25654048

  10. The Risk and Clinical and Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

    DTIC Science & Technology

    2013-10-01

    Neurofibromatosis type 1 ( NF1 ) in a multi- institutional setting. The first aim is to assess the incidence of breast cancer in this cohort and the clinical...features of NF1 associated with breast cancer. The second aim is to investigate any characteristic NF1 gene germline mutations in women with breast cancer...the selected signaling pathway on archived breast cancer tissue from women with NF1 utilizing immunohistochemistry (IHC) methods. At the somatic level

  11. Genetic Evaluation of Peripheral Nerve Sheath Tumors in Neurofibromatosis Type I

    DTIC Science & Technology

    2003-10-01

    neurofibromatosis type 1 (NF1). Archival and prospectively acquired plexiform neurofibromas and malignant peripheral nerve sheath tumors ( MPNSTs ) were collected...evaluated, whereas a relatively small number of MPNSTs have been collected for complete analysis. Immunohistochemical stains have been developed to...distinguish -high-grade versus low-grade MPNSTs and plexiform neurofibromas. The genome of plexiform neurofibromas is relatively stable, compared to the

  12. Cilioretinal Artery Territory Infarction Associated With Papilledema in a Patient With Neurofibromatosis Type 2.

    PubMed

    Mahroo, Omar A; Mohamed, Moin D; Graham, Elizabeth M; Mann, Samantha S; Plant, Gordon T; Afridi, Shazia K; Hammond, Christopher J

    2016-03-01

    Cilioretinal artery territory infarction can occur in isolation or in association with other vascular compromise of the retinal circulation. Our patient, an 18-year-old woman with neurofibromatosis type 2, developed a cilioretinal artery territory infarction in the setting of papilledema. Our case, together with one previous report, suggests that cilioretinal artery territory infarction in the context of papilledema, although rare, is a real entity.

  13. What’s New in Neurofibromatosis? Proceedings From The 2009 NF Conference: New Frontiers

    PubMed Central

    Kissil, Joseph; Blakeley, Jaishri; Ferner, Rosalie; Huson, Susan; Kalamarides, Michel; Mautner, Victor-Felix; McCormick, Frank; Morrison, Helen; Packer, Roger; Ramesh, Vijaya; Ratner, Nancy; Rauen, Katherine A.; Stevenson, David; Hunter-Schaedle, Kim; North, Kathryn

    2009-01-01

    The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been convened by the Children’s Tumor Foundation for over 20 years. The 2009 NF Conference was held in Portland, Oregon from June 13th – June 16th, 2009 and co-chaired by Kathryn North from the University of Sydney and The Children’s Hospital at Westmead, Sydney, Australia; and Joseph Kissil from the Wistar Institute, Philadelphia. The Conference included 80 platform presentations in 9 sessions over 4 days; over 100 abstracts presented as posters; and three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromatosis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical researchers. Correspondingly the NF Conference scope has expanded to include translational research, clinical trials and clinical management issues while retaining a core of basic research. These themes are reflected in the highlights from the 2009 NF Conference presented here. PMID:20082461

  14. Malignant nerve-sheath neoplasms in neurofibromatosis: distinction from benign tumors by using imaging techniques

    SciTech Connect

    Levine, E.; Huntrakoon, M.; Wetzel, L.H.

    1987-11-01

    Malignant peripheral nerve-sheath neoplasms frequently complicate neurofibromatosis causing pain, enlarging masses, or neurologic deficits. However, similar findings sometimes also occur with benign nerve neoplasms. Our study was done retrospectively to determine if imaging techniques can differentiate malignant from benign nerve tumors in neurofibromatosis. Eight patients with symptomatic neoplasms (three benign, five malignant) were studied by CT in eight, MR in six, and /sup 67/Ga-citrate scintigraphy in seven. Uptake of /sup 67/Ga occurred in all five malignant lesions but not in two benign neoplasms studied. On CT or MR, all eight lesions, including three benign neoplasms, showed inhomogeneities. Of five lesions with irregular, infiltrative margins on CT or MR, four were malignant and one was benign. Of three lesions with smooth margins, one was malignant and two were benign. One malignant neoplasm caused irregular bone destruction. Accordingly, CT and MR could not generally distinguish malignant from benign lesions with certainty. However, both CT and MR provided structural delineation to help surgical planning for both types of lesion. /sup 67/Ga scintigraphy appears promising as a screening technique to identify lesions with malignant degeneration in patients with neurofibromatosis. Any area of abnormal radiogallium uptake suggests malignancy warranting further evaluation by CT or MR. Biopsy of any questionable lesion is essential.

  15. What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers.

    PubMed

    Kissil, Joseph L; Blakeley, Jaishri O; Ferner, Rosalie E; Huson, Susan M; Kalamarides, Michel; Mautner, Victor-Felix; McCormick, Frank; Morrison, Helen; Packer, Roger; Ramesh, Vijaya; Ratner, Nancy; Rauen, Katherine A; Stevenson, David A; Hunter-Schaedle, Kim; North, Kathryn

    2010-02-01

    The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been convened by the Children's Tumor Foundation for over 20 years. The 2009 NF Conference was held in Portland, Oregon from June 13 to June 16, 2009 and co-chaired by Kathryn North from the University of Sydney and The Children's Hospital at Westmead, Sydney, Australia; and Joseph Kissil from the Wistar Institute, Philadelphia. The Conference included 80 platform presentations in 9 sessions over 4 days; over 100 abstracts presented as posters; and three Keynote presentations. To date, there have been tremendous advances in basic research in the pathogenesis of neurofibromatosis, and more recently in progress toward identifying effective drug therapies and the commencement of neurofibromatosis clinical trials. The NF Conference attendees have significantly increased (doubling from 140 in 2005 to 280 attending in 2009) with a significant increase in attendance of physicians and clinical researchers. Correspondingly the NF Conference scope has expanded to include translational research, clinical trials and clinical management issues while retaining a core of basic research. These themes are reflected in the highlights from the 2009 NF Conference presented here.

  16. Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I.

    PubMed

    Gales, Jordan; Prayson, Richard A

    2017-03-01

    Neurofibromatosis type I (NF1) is a relatively common disorder associated with a range of neurologic sequelae. Refractory epilepsy occurs in 4-13% of NF1 patients. Hippocampal sclerosis and focal cortical dysplasia, both well-defined epilepsy-related entities, have been described in a subset of cases. To our knowledge, there has been only one other series describing coexistent focal cortical dysplasia and hippocampal sclerosis in the setting of NF1. We report two such patients who presented with intractable seizures requiring epilepsy surgery. Histologically, the hippocampal sclerosis specimen met criteria for the International League Against Epilepsy (ILAE) hippocampal sclerosis subtypes Ia and II respectively. The associated focal cortical dysplasia observed within the resected temporal lobe were both consistent with ILAE focal cortical dysplasia type IIIa (e.g. associated with a secondary lesion). Post-operatively, both patients had recurrence of habitual seizures, with one case continuing to have intractable seizures following two subsequent temporal lobectomies. Although hippocampal sclerosis association with focal cortical dysplasia is well document in epilepsy, it has been rarely described in the setting of neurofibromatosis type I. Although prior surgical series have shown good epilepsy surgery outcomes within neurofibromatosis type I, these two cases did not.

  17. Growth in North American white children with neurofibromatosis 1 (NF1)

    PubMed Central

    Szudek, J; Birch, P; Friedman, J; Participants, t. N.

    2000-01-01

    OBJECTIVE—To analyse the distributions of and generate growth charts for stature and occipitofrontal circumference (OFC) in neurofibromatosis 1 (NF1) patients.
DESIGN—Cross sectional database survey.
SETTING—The National Neurofibromatosis Foundation International Database (NFDB) includes clinical information on NF1 patients from 14 participating centres in North America.
SUBJECTS—A total of 569 white, North American, NF1 patients, 55% female and 45% male.
MAIN OUTCOME MEASURES—Stature and OFC measurements of NF1 patients were compared to age and sex matched population norms using z score standardisation and centile curves.
RESULTS—The distributions of stature and OFC are shifted and unimodal among NF1 patients; 13% of patients have short stature (⩾2 standard deviations below the population mean) and 24% have macrocephaly (OFC ⩾2 standard deviations above the population mean).
CONCLUSIONS—Alterations of stature and OFC are not limited to NF1 patients with frank short stature or macrocephaly.


Keywords: neurofibromatosis 1; stature; occipitofrontal circumference; macrocephaly PMID:11106357

  18. Poor wound healing after pial synangiosis in 2 children with moyamoya vasculopathy associated with neurofibromatosis type 1.

    PubMed

    Golomb, Meredith R; Smith, Jodi L

    2014-10-01

    Wound healing is a key component of recovery for children with neurologic conditions undergoing neurosurgical procedures. Understanding factors that can impair wound healing aids in planning long-term clinical care. Children with neurofibromatosis type 1 are at risk for vasculopathies in the brain (including moyamoya vasculopathy) and in other organs, including the heart, lung, and skin. Neurofibromatosis 1 is caused by mutations in the gene for neurofibromin, a protein that plays a role in tissue maintenance and repair as well as tumor suppression. The authors report 2 children with neurofibromatosis 1-associated moyamoya vasculopathy who developed significant wound healing complications after pial synangiosis surgery. They discuss possible contributors to these complications, including the role of neurofibromin and the possibility of vasculopathy affecting the skin, and the implications of poor wound healing in pediatric neurology patients.

  19. Spontaneous Rupture of the Hepatic Artery in a Patient with Type 1 Neurofibromatosis Treated by Embolization: A Case Report

    SciTech Connect

    Rao, V. Day, C.P.; Manimaran, N.; Hurlow, R.A.; Orme, R.

    2007-02-15

    We report the case of a 48-year-old man with neurofibromatosis presenting with sudden-onset abdominal pain, profound hypotension, and a drop in hemoglobin. CT scan demonstrated a massive hematoma within the right lobe of the liver with rupture into the peritoneal cavity. Angiography demonstrated diffuse abnormalities of the hepatic circulation with fusifom, ectatic, and stenotic segments. Acute extravasation from a peripheral branch of the right hepatic artery was identified and successfully embolized with subsequent hemodynamic stabilization of the patient. To the best of our knowledge this is the first case report of this kind in a patient with type I neurofibromatosis.

  20. Genetic inhibition of Anaplastic Lymphoma Kinase rescues cognitive impairments in Neurofibromatosis 1 mutant mice.

    PubMed

    Weiss, Joseph B; Weber, Sydney J; Torres, Eileen Ruth S; Marzulla, Tessa; Raber, Jacob

    2017-03-15

    Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations occur in approximately 90% of patients with neurofibromatosis. A major, disabling phenotypic consequence of reduced NF1 function is cognitive impairment; a possibly related behavioral phenotype is impaired sleep. Recent results in Drosophila have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 for both associative learning and sleep. Inhibition of Alk improves associative learning and sleep in heterozygous NF1 mutant flies. The results in Drosophila provide a strong motivation to investigate NF1/Alk genetic interactions in mice. In Drosophila, activation of Alk by its ligand, Jelly belly (Jeb), is the physiologically relevant target of negative regulation by NF1. Therefore, we tested whether genetic inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments in mice. Our results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras. The cognitive phenotypes observed in heterozygous NF1 mutant mice are rescued or ameliorated by genetic inhibition of Alk activity. In two tests of hippocampus-dependent learning, the Morris water maze and extinction of contextual fear, mutation of one or both alleles of Alk was sufficient to improve performance to wild type or near wild type levels in NF1-/+ mice. In addition, in NF1 mice genetic inhibition of Alk improves circadian activity levels. These data are intriguing in light of the circadian alterations seen in NF1 patients and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.

  1. Sensitivity of cultured skin fibroblasts from patients with neurofibromatosis to DNA-damaging agents

    SciTech Connect

    Woods, W.G.; McKenzie, B.; Letourneau, M.A.; Byrne, T.D.

    1986-01-01

    Neurofibromatosis (NF) is an autosomal dominant disorder associated with various constitutional abnormalities as well as a striking predisposition for malignant and nonmalignant neoplasms, both in cells originating in and not originating in the neural crest. We have examined the sensitivity of cultured skin fibroblasts from patients with neurofibromatosis to several types of DNA damage. Fibroblasts in Dulbecco's modified Eagle's medium were plated at 10(2) to 2 X 10(4) cells per 75 cm2 tissue culture plates, and exposed to various doses of gamma radiation (leads to DNA scission), actinomycin D, or mitomycin C. Cells were reincubated for 15 to 40 days until surviving colonies exhibited greater than 30-50 cells. Plates were then stained with 1% methylene blue and the colonies counted, with surviving fraction determined relative to plating efficiency. Nine skin fibroblast cell strains from normal individuals were studied as controls. One neurofibromatosis (NF) cell strain, SB23, exhibited normal sensitivity to all three DNA-damaging agents studied in early (7-8) and middle (12-13) in vitro passage. Strain GM0622, on the other hand, exhibited normal sensitivity to the three DNA-damaging agents studied at early passage, but showed a significant decrease in survival after exposure to both gamma radiation (D0 = 106 rad) and actinomycin D (D0 = 0.024 mcg/ml) with increasing passage. Strain GM1639 exhibited decreased survival after actinomycin D exposure at early passage (D0 = 0.017 mcg/ml), with normal survival after exposure to gamma radiation and mitomycin C at the same passage.

  2. The Risk and Clinical/Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

    DTIC Science & Technology

    2015-09-01

    1 Award Number: W81XWH-11-1-0671 TITLE: The Risk and Clinical /Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1...DATES COVERED 30 Sep 2014 – 18 Aug 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-11-1-0671 “The Risk and Clinical /Molecular...cancer in this cohort and the clinical features of NF1 associated with breast cancer and other cancers. A total of 423 cases of NF1 women have been

  3. The Risk and Clinical/Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

    DTIC Science & Technology

    2016-03-01

    1 Award Number: W81XWH-11-1-0671 TITLE: The Risk and Clinical /Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1...30Sep2011 - 31Dec2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-11-1-0671 “The Risk and Clinical /Molecular Characteristics of Breast Cancer...a multi- institutional setting. Aim 1 assessed the incidence of breast cancer in this cohort and the clinical features of NF1 associated with breast

  4. Peripheral retinal ischemia in a young Indian woman with neurofibromatosis type 1☆☆☆

    PubMed Central

    Seth, Anisha; Ghosh, Basudeb; Gupta, Anika; Goel, Neha

    2015-01-01

    Neurofibromatosis type 1 (NF-1) is an autosomal dominantly inherited disease characterized by café-au-lait spots, neurofibromas, axillary freckling, Lisch nodules of iris, gliomas and various systemic vascular ischemic manifestations mainly in the aorta, brain and kidney. Retinal vascular manifestations in patients with NF-1 are usually representative of retinal capillary hemangiomatosis. Few cases of NF-1 with retinal vascular occlusive disease have been described. We describe a young Indian woman with NF-1 with unilateral peripheral retinal ischemia but no vascular abnormality at the posterior pole. PMID:26949362

  5. Juvenile Xanthogranuloma in a Child with Previously Unsuspected Neurofibromatosis Type 1 and Juvenile Myelomonocytic Leukemia

    PubMed Central

    Arthur, Diane C.; Wayne, Alan S.; Rennert, Owen M.; Toretsky, Jeffrey A.; Stratakis, Constantine A.

    2009-01-01

    The association of neurofibromatosis 1 (NF1), juvenile xanthogranulomas (JXG), and juvenile myelomonocytic leukemia (JMML) has been previously reported. We describe herein this triad in a Caucasian male infant with a pathogenic mutation in the NF1 gene (neurofibromin). The clinical course from initial presentation to final diagnosis is detailed; the physical features and hematological characteristics are discussed. The patient underwent bone marrow transplantation and is currently in remission. Children with concurrent cutaneous café-au-lait and JXG lesions should be evaluated and monitored closely for the possible development of JMML. PMID:19785027

  6. Giant Extracranial Aneurysm of the Internal Carotid Artery in Neurofibromatosis Type 1

    PubMed Central

    Moratti, C.; Andersson, T.

    2012-01-01

    Summary Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder characterized by cutaneous pigmentations, neurofibromas, Lisch nodules and neuroectodermal tumors. Supra-aortic vessel aneurysms may affect patients with NF-1 and can be associated with rupture, ischemic complications and compression symptoms. We describe a 48-year-old woman with NF-1 and an extracranial 3×5 cm right internal carotid artery aneurysm. After balloon test occlusion the patient was treated with parent artery sacrifice which led to significant shrinkage on follow-up MR and reduction of compression symptoms. The literature concerning internal carotid artery aneurysms associated with NF-1 is reviewed evaluating the possible therapeutic options. PMID:22958775

  7. COMT Val158Met Polymorphism Is Associated with Verbal Working Memory in Neurofibromatosis Type 1

    PubMed Central

    Costa, Danielle de Souza; de Paula, Jonas J.; Alvim-Soares, Antonio M.; Pereira, Patrícia A.; Malloy-Diniz, Leandro F.; Rodrigues, Luiz O. C.; Romano-Silva, Marco A.; de Miranda, Débora M.

    2016-01-01

    Neurofibromatosis type I (NF1) is a neurogenetic disease marked by multiple cognitive and learning problems. Genetic variants may account for phenotypic variance in NF1. Here, we investigated the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and working memory and arithmetic performance in 50 NF1 individuals. A significant association of the COMT polymorphism was observed only with verbal working memory, as measured by the backward digit-span task with an advantageous performance for Met/Met carriers. To study how genetic modifiers influence NF1 cognitive performance might be of importance to decrease the unpredictability of the cognitive profile among NF1 patients. PMID:27458360

  8. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2†

    PubMed Central

    Mautner, Victor-Felix; Nguyen, Rosa; Kutta, Hannes; Fuensterer, Carsten; Bokemeyer, Carsten; Hagel, Christian; Friedrich, Reinhard E.; Panse, Jens

    2010-01-01

    Bilateral vestibular schwannomas are the hallmark of neurofibromatosis type 2 (NF2), and these tumors impair hearing and frequently lead to deafness. Neurosurgical intervention, the only established treatment, often damages the vestibular nerve. We report 2 cases in which treatment with bevacizumab (for 3 months in one case and 6 months in the other) induced regression of progressive vestibular schwannomas by more than 40% and substantially improved hearing in the patient treated for 6 months. Bevacizumab therapy may thus provide an effective treatment for progressive vestibular schwannomas in patients with NF2. PMID:20150363

  9. Case of pigmented neurofibroma with hypertrichosis with no association to neurofibromatosis.

    PubMed

    Na, Chan Ho; Song, In Guk; Chung, Byoung Soo; Shin, Bong Seok

    2009-10-01

    Pigmented neurofibroma (PNF) is a rare cutaneous tumor that has been observed in patients with or without neurofibromatosis (NF). This tumor is histologically characterized by the coexistence of scattered melanin-laden cells and benign spindle cells with neural differentiations. Hypertrichosis is the excessive growth of hair on non-androgen-dependent areas of the body. It has been reported that hypertrichosis may sometimes overlie a neurofibroma. We highlight a case of PNF with hypertrichosis on a 17-year-old woman with no associated NF. We also discuss the possible underlying pathogenic mechanism of a localized hypertrichosis in PNF patients.

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

    PubMed Central

    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

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

    PubMed

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

    2014-08-01

    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.

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

    PubMed Central

    Rangarajan, Vithal; Mahore, Amit; Patil, Manoj; Sathe, Prashant; Kaswa, Amol; Gore, Sandeep; Dharurkar, Pralhad; Kawale, Juhi

    2015-01-01

    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. PMID:26600957

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

    PubMed Central

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

    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 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. PMID:26955185

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

    PubMed Central

    Chammas, Majid Z.; Robken, Jon; Coyne, Edmund

    2016-01-01

    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. PMID:27867667

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

    ERIC Educational Resources Information Center

    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…

  16. Neurocognitive outcomes in neurofibromatosis clinical trials: Recommendations for the domain of attention.

    PubMed

    Walsh, Karin S; Janusz, Jennifer; Wolters, Pamela L; Martin, Staci; Klein-Tasman, Bonita P; Toledo-Tamula, Mary Anne; Thompson, Heather L; Payne, Jonathan M; Hardy, Kristina K; de Blank, Peter; Semerjian, Claire; Gray, Laura Schaffner; Solomon, Sondra E; Ullrich, Nicole

    2016-08-16

    Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials.

  17. Enhanced response to the induction of sister chromatid exchange by gamma radiation in neurofibromatosis

    SciTech Connect

    Hafez, M.; Abd el-Nabi, S.M.; el-Wehedi, G.; Al-Tonbary, Y.

    1986-05-15

    The study included 8 unrelated patients with neurofibromatosis, and 10 unrelated normal and healthy persons as controls. Whole blood samples were divided into plastic T flasks and exposed at room temperature to gamma rays. The radiation dose was 36 rad/minute, and the doses delivered were 0, 75, 150 and 300 rad. The lymphocytes were cultured in (RPMI) 1640 tissue culture medium and autologous serum (20%). Phytohemagglutinin and bromodeoxyuridine (Brdu) (10 microM) were added at initiation of culture and harvesting was done 64 to 68 hours after culture initiation. Slides were coded, differential staining was done, and sister chromatid exchanges (SCEs) and aberrations (gaps, breaks, dicentrics, fragments and minutes) were counted. In the controls no significant increase in frequency of SCE has been found (P greater than 0.5). In the patients, the frequencies significantly increased with the increase of dose of irradiation (P less than 0.001). Furthermore, after irradiation, the incidence of gaps, breaks, and dicentrics were significantly increased in patients compared with controls. Moreover, the incidence increased with the increase in the dose of radiation. The results are discussed with a conclusion that the results add to the indication of a genetic predisposition to develop cancer in neurofibromatosis patients.

  18. Hybrid neurofibroma/schwannoma is overrepresented among schwannomatosis and neurofibromatosis patients.

    PubMed

    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.

  19. Arterial hypertension and neurofibromatosis: renal artery stenosis and coarctation of abdominal aorta.

    PubMed Central

    Schürch, W.; Messerli, F. H.; Genest, J.; Lefebvre, R.; Roy, P.; Carter, P.; Rojo-Ortega, J. M.

    1975-01-01

    A 10-year-old girl had arterial hypertension, generalized neurofibromatosis, coarctation of the abdominal aorta and multiple stenoses at the origin of each renal artery. After resection of the stenotic areas and reimplantation of the renal arteries in the aorta, her arterial pressure decreased substantially. However, hypertension recurred and radiologic follow-up 4 1/2 years later showed distinct progression of the coarctation and renewed stenosis of all renal arteries at their origin. The stenotic areas showed eccentric intimal proliferation, frequently bulging into the lumen, with small nodular aggregates of smooth muscle cells and proliferation of fibrous tissue containing spindle-shaped nuclei in a palisading pattern. Hypertension associated with neurofibromatotic vascular disease has been described in 47 other patients in the literature. These patients have been young (mean age, 14 years) and predominantly male. In contrast to fibromuscular dysplasia, in which 95% of all stenoses are found in the distal two thirds of the renal arteries, in vascular neurofibromatosis more than 50% of the stenoses are found at the origin. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 PMID:810239

  20. Neurofibromatosis Type 1: A Novel NF1 Mutation Associated with Mitochondrial Complex I Deficiency

    PubMed Central

    Isidoro, Lara; Rocha, Dalila

    2014-01-01

    Background. Neurofibromatosis type 1 is a multisystemic, progressive disease, with an estimated incidence of 1/3500-2500. Mitochondrial diseases are generally multisystemic and may be present at any age, and the global prevalence is 1/8500. The diagnosis of these disorders is complex because of its clinical and genetic heterogeneity. Case Report. We present a rare case of the association of these two different genetic diseases, in which a heterozygous missense mutation in the NF1 gene was identified which had not yet been described (p.M1149 V). Additionally, the patient is suspected of carrying an unspecified mutation causing respiratory chain complex I deficiency. Clinical presentation included hypotonia, global development delay, reduced growth rate, progressive microcephaly, and numerous café-au-lait spots. Discussion. To the best of our knowledge this is the first report of complex I deficiency in a patient with neurofibromatosis type 1. It is very important to maintain a high index of suspicion for the diagnosis of mitochondrial disorders. In this patient, both the laboratory screening and muscle histology were normal and only the biochemical study of muscle allowed us to confirm the diagnosis. PMID:24711935

  1. Endovascular Treatment of a Ruptured Internal Thoracic Artery Pseudoaneurysm Presenting as a Massive Hemothorax in a Patient with Type I Neurofibromatosis

    SciTech Connect

    Kim, Soo Jin; Kim, Chang Won Kim, Suk; Lee, Tae Hong; Kim, Kun Il; Moon, Tae Yong; Chung, Sung Woon

    2005-12-15

    We report a case of acute hemothorax caused by a left internal thoracic artery pseudoaneurysm rupture in a patient with neurofibromatosis type I, which was successfully treated with endovascular coil embolization.

  2. Discovery of Novel Drugs to Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis

    DTIC Science & Technology

    2015-08-01

    AWARD NUMBER: W81XWH-13-1-0113 TITLE: Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin...Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis 5a...include area code) 1 Table of contents Table of contents 1 Introduction 2 Overall Summary 2 Body 4 β-catenin is activated during tibial

  3. Planificación Neuroquirúrgica con Software Osirix

    PubMed Central

    Jaimovich, Sebastián Gastón; Guevara, Martin; Pampin, Sergio; Jaimovich, Roberto; Gardella, Javier Luis

    2014-01-01

    Introducción: La individualidad anatómica es clave para reducir el trauma quirúrgico y obtener un mejor resultado. Actualmente, el avance en las neuroimágenes ha permitido objetivar esa individualidad anatómica, permitiendo planificar la intervención quirúrgica. Con este objetivo, presentamos nuestra experiencia con el software Osirix. Descripción de la técnica: Se presentan 3 casos ejemplificadores de 40 realizados. Caso 1: Paciente con meningioma de la convexidad parasagital izquierda en área premotora; Caso 2: Paciente con macroadenoma hipofisario, operada previamente por vía transeptoesfenoidal en otra institución con una resección parcial; Caso 3: Paciente con lesiones en pedúnculo cerebeloso medio bilateral. Se realizó la planificación prequirúrgica con el software OsiriX, fusionando y reconstruyendo en 3D las imágenes de TC e IRM, para analizar relaciones anatómicas, medir distancias, coordenadas y trayectorias, entre otras funciones. Discusión: El software OsiriX de acceso libre y gratuito permite al cirujano, mediante la fusión y reconstrucción en 3D de imágenes, analizar la anatomía individual del paciente y planificar de forma rápida, simple, segura y económica cirugías de alta complejidad. En el Caso 1 se pudo analizar las relaciones del tumor con las estructuras adyacentes para minimizar el abordaje. En el Caso 2 permitió comprender la anatomía post-operatoria previa del paciente, para determinar la trayectoria del abordaje transnasal endoscópico y la necesidad de ampliar su exposición, logrando la resección tumoral completa. En el Caso 3 permitió obtener las coordenadas estereotáxicas y trayectoria de una lesión sin representación tomográfica. Conclusión: En casos de no contar con costosos sistemas de neuronavegación o estereotáxia el software OsiriX es una alternativa a la hora de planificar la cirugía, con el objetivo de disminuir el trauma y la morbilidad operatoria. PMID:25165617

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

    PubMed

    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

  5. Characterization of six mutations in Exon 37 of neurofibromatosis type 1 gene

    SciTech Connect

    Upadhyaya, M.; Osborn, M.; Maynard, J.; Harper, P.

    1996-07-26

    Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders, with an incidence of 1 in 3,000. We screened a total of 320 unrelated NF1 patients for mutations in exon 37 of the NF1 gene. Six independent mutations were identified, of which three are novel, and these include a recurrent nonsense mutation identified in 2 unrelated patients at codon 2281 (G2281X), a 1-bp insertion (6791 ins A) resulting in a change of TAG (tyrosine) to a TAA (stop codon), and a 3-bp deletion (6839 del TAC) which generated a frameshift. Another recurrent nonsense mutation, Y2264X, which was detected in 2 unrelated patients in this study, was also previously reported in 2 NF1 individuals. All the mutations were identified within a contiguous 49-bp sequence. Further studies are warranted to support the notion that this region of the gene contains highly mutable sequences. 17 refs., 2 figs., 1 tab.

  6. Unilateral gynecomastia and pseudoangiomatous stromal hyperplasia in neurofibromatosis: case report and review of the literature.

    PubMed

    Kimura, Satoshi; Tanimoto, Akihide; Shimajiri, Shohei; Sasaguri, Takakazu; Yamada, Sohsuke; Wang, Ke-Yong; Guo, Xin; Sasaguri, Yasuyuki

    2012-05-15

    In this article, we describe unilateral gynecomastia and pseudoangiomatous stromal hyperplasia (PASH) in a case of type-1 neurofibromatosis (NF-1). It is important to distinguish PASH from fibroadenoma clinically, and from true blood capillaries and angiosarcoma histologically. In the present case, giant multinucleated cells lined the pseudovascular spaces, which was markedly different from that of conventional breast PASH. The origin of PASH has been reported to be either the fibroblast or the myofibroblast phenotype and may be affected by endocrine signaling because many cases have been reported in premenopausal women, and cases are often estrogen (ER) and progesterone receptor (PR) positive. However, previous reports have identified PASH in NF-1 in juvenile males only, and the cases were negative for α-SMA, ER and PR. The cause and prognosis of PASH in NF-1 may be distinguished from that of conventional PASH, and mast cells, histiocytes and CD54 may play roles.

  7. Vertebral Arteriovenous Fistula Associated with Neurofibromatosis Type I Misdiagnosed as a Giant Aneurysm *

    PubMed Central

    Benndorf, G.; Assmann, U.; Bender, A.; Lehmann, T. N.; Lanksch, W. R.

    2000-01-01

    Summary A 59-year-old man with neurofibromatosis type 1 (NF1) presented with bruits and neck pain due to a space occupying lesion in the right neck tissue. Digital subtraction angiography (DSA) showed an arteriovenous fistula (AVF) of the right extracranial vertebral artery (VA) with a giant venous pouch and an intracranial berry aneurysm of the right middle cerebral artery (MCA). First, the MCA aneurysm was surgically clipped, then the patient was treated by embolisation with coils. The coils were placed transarterially from the left VA resulting in a partial thrombosis of the venous pouch. Complete closure was achieved secondarily by retrograde transvenous catheterization. Etiology and treatment modalities are discussed. PMID:20667184

  8. Dystrophic thoracic spine dislocation associated with type-1 neurofibromatosis: Case report and rationale for treatment.

    PubMed

    Meneses-Quintero, David; Alvarado-Gómez, Fernando; Alcalá-Cerra, Gabriel

    2015-01-01

    The authors report a rare case of spontaneous dystrophic thoracic spine dislocation in a 14-year-old boy with neurofibromatosis type 1 (NF-1). Anteroposterior and lateral standing radiographs showed a dysplastic kyphoscoliotic deformity, with the thoracic kyphosis and scoliosis measuring 75° and 69°, respectively. Three-dimensional reconstruction after computed tomography demonstrated spondyloptosis at T5-T6 with overlapping of T5 over T6 and T7. The patient underwent circumferential fusion with anterior fibular strut grafting mechanically secured between the inferior and superior endplates of T5 and T7 followed by an instrumented posterior fusion from T2 to L1 and thoracoplasty. There was satisfactory resolution of the deformity with stabilization at the last follow-up evaluation.

  9. Dystrophic thoracic spine dislocation associated with type-1 neurofibromatosis: Case report and rationale for treatment

    PubMed Central

    Meneses-Quintero, David; Alvarado-Gómez, Fernando; Alcalá-Cerra, Gabriel

    2015-01-01

    The authors report a rare case of spontaneous dystrophic thoracic spine dislocation in a 14-year-old boy with neurofibromatosis type 1 (NF-1). Anteroposterior and lateral standing radiographs showed a dysplastic kyphoscoliotic deformity, with the thoracic kyphosis and scoliosis measuring 75° and 69°, respectively. Three-dimensional reconstruction after computed tomography demonstrated spondyloptosis at T5-T6 with overlapping of T5 over T6 and T7. The patient underwent circumferential fusion with anterior fibular strut grafting mechanically secured between the inferior and superior endplates of T5 and T7 followed by an instrumented posterior fusion from T2 to L1 and thoracoplasty. There was satisfactory resolution of the deformity with stabilization at the last follow-up evaluation. PMID:25972714

  10. Epilepsy Mechanisms in Neurocutaneous Disorders: Tuberous Sclerosis Complex, Neurofibromatosis Type 1, and Sturge–Weber Syndrome

    PubMed Central

    Stafstrom, Carl E.; Staedtke, Verena; Comi, Anne M.

    2017-01-01

    Neurocutaneous disorders are multisystem diseases affecting skin, brain, and other organs. Epilepsy is very common in the neurocutaneous disorders, affecting up to 90% of patients with tuberous sclerosis complex (TSC) and Sturge–Weber syndrome (SWS), for example. The mechanisms underlying the increased predisposition to brain hyperexcitability differ between disorders, yet some molecular pathways overlap. For instance, the mechanistic target of rapamycin (mTOR) signaling cascade plays a central role in seizures and epileptogenesis in numerous acquired and genetic disorders, including several neurocutaneous disorders. Potential routes for target-specific treatments are emerging as the genetic and molecular pathways involved in neurocutaneous disorders become increasingly understood. This review explores the clinical features and mechanisms of epilepsy in three common neurocutaneous disorders—TSC, neurofibromatosis type 1, and SWS. PMID:28367137

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

    PubMed Central

    Ricker, Cora A.; Pan, Yuan; Gutmann, David H.; Keller, Charles

    2016-01-01

    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 (LGGs; pilocytic astrocytoma) 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 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. PMID:28066715

  12. Oral manifestations of neurofibromatosis type 1 in children with facial plexiform neurofibroma: report of three cases.

    PubMed

    Cunha, K S; Rozza-de-Menezes, R E; Andrade, R M; Almeida, Lms; Janini, Mer; Geller, M

    2015-01-01

    Neurofibromatosis type 1 (NF1) is a common autosomal genetic disorder with a prevalence of 1 in 3,000 births. NF1 is a complex syndrome characterized by many abnormalities and may affect all organ systems. Oral manifestations of NF1 occur frequently, but reports including NF1 children with facial plexiform neurofibromas and oral alterations are scant. Facial plexiform neurofibroma may cause asymmetry, disfigurement and usually arises from the trigeminal nerve. The aim of this paper is to to report three pediatric NF1 cases with facial plexiform neurofibroma presenting with oral manifestations, which were evaluated clinically and radiographically, and also to briefly review the literature. Patients presented with changes in the oral soft tissues, jaws, and teeth ipsilateral to the tumor.

  13. Superficial malignant peripheral nerve sheath tumor arising from diffuse neurofibroma in a neurofibromatosis type 1 patient.

    PubMed

    Inoue, Takuya; Kuwashiro, Maki; Misago, Noriyuki; Narisawa, Yutaka

    2014-07-01

    Malignant peripheral nerve sheath tumors (MPNST) are regarded as sarcomas that arise from peripheral nerves or that display differentiation along the lines of the various elements of the nerve sheath. These tumors occur in deep soft tissues, but superficial primary MPNST with a cutaneous or subcutaneous origin have rarely been reported. A 70-year-old woman presented with a 3-4-year history of a slowly enlarging soft nodule on the left side of her neck. The histopathological diagnosis of the nodule was low-grade MPNST arising from diffuse neurofibroma. There was increased cellularity, but no necrosis or mitotic activity. These histopathological findings pose difficulties in differential diagnosis from a neurofibroma with atypical histological features. We report a rare case of superficial MPNST arising from diffuse neurofibroma associated with underlying occipital bone dysplasia in a neurofibromatosis type 1 patient.

  14. PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice.

    PubMed

    Brown, Jacquelyn A; Xu, Jinbin; Diggs-Andrews, Kelly A; Wozniak, David F; Mach, Robert H; Gutmann, David H

    2011-12-01

    Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [(11)C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and l-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD.

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

    PubMed

    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.

  16. The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing.

    PubMed Central

    Skuse, G R; Cappione, A J; Sowden, M; Metheny, L J; Smith, H C

    1996-01-01

    A functional mooring sequence, known to be required for apolipoprotein B (apoB) mRNA editing, exists in the mRNA encoding the neurofibromatosis type I (NF1) tumor suppressor. Editing of NF1 mRNA modifies cytidine in an arginine codon (CGA) at nucleotide 2914 to a uridine (UGA), creating an in frame translation stop codon. NF1 editing occurs in normal tissue but was several-fold higher in tumors. In vitro editing and transfection assays demonstrated that apoB and NF1 RNA editing will take place in both neural tumor and hepatoma cells. Unlike apoB, NF1 editing did not demonstrate dependence on rate-limiting quantities of APOBEC-1 (the apoB editing catalytic subunit) suggesting that different trans-acting factors may be involved in the two editing processes. PMID:8602361

  17. Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene.

    PubMed Central

    Upadhyaya, M; Maynard, J; Osborn, M; Huson, S M; Ponder, M; Ponder, B A; Harper, P S

    1995-01-01

    Neurofibromatosis type 1 is one of the most common inherited disorders with an incidence of 1 in 3000. The search for NF1 mutations has been hampered by the overall size of the gene, the large number of exons, and the high mutation rate. To date, fewer than 90 mutations have been reported to the NF1 mutation analysis consortium and the details on 76 mutations have been published. We have identified five new mutations using single strand conformation polymorphism (SSCP) and heteroduplex analysis (HA) and three intragenic deletions with the microsatellite markers. Of the five new mutations, two were in exon 27a, two in exon 45, and one in exon 49 and these include 4630delA, 4572delC, R7846X, T7828A, and one in the 3' untranslated region (3' UTR). The two nucleotide alterations in exon 27a and the one in exon 45 are predicted to produce a truncated protein. Images PMID:8544190

  18. PET Imaging for Attention Deficit Preclinical Drug Testing in Neurofibromatosis-1 Mice

    PubMed Central

    Brown, Jacquelyn A.; Xu, Jinbin; Diggs-Andrews, Kelly A.; Wozniak, David F.; Mach, Robert H.; Gutmann, David H.

    2011-01-01

    Attention system abnormalities represent a significant barrier to scholastic achievement in children with neurofibromatosis-1 (NF1). Using a novel mouse model of NF1-associated attention deficit (ADD), we demonstrate a presynaptic defect in striatal dopaminergic homeostasis and leverage this finding to apply [11C]-raclopride positron-emission tomography (PET) in the intact animal. While methylphenidate and L-Deprenyl correct both striatal dopamine levels on PET imaging and defective attention system function in Nf1 mutant mice, pharmacologic agents that target de-regulated cyclic AMP and RAS signaling in these mice do not. These studies establish a robust preclinical model to evaluate promising agents for NF1-associated ADD. PMID:21963652

  19. Screening for somatic mutations of the neurofibromatosis genes in nervous system and other solid tumors

    SciTech Connect

    Rangaratnam, S.; Narod, S.; Ruttledge, M.

    1994-09-01

    Von Recklinghausen neurofibromatosis (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant inherited disorders which predispose carriers to various benign and malignant tumors. Both genes are thought to act as tumor suppressors with inactivation of both alleles resulting in abnormal cell growth. By inference from other hereditary cancer syndromes, it has been hypothesized that somatic mutation at the NF1 and NF2 loci is involved in the development of sporadic tumors of the types found with increased prevalence in these disorders. In addition to other malignancies, individuals with NF1 are at increased risk to develop astrocytomas and rhabdomyosarcomas. We have therefore screened 40 astrocytomas for LOH using three NF1-derived cDNA probes, and have found no abnormalities. Single-strand conformation polymorphism (SSCP) analysis of exons of the NF1 GAP-related domain has also failed to show any variants in a total of 70 astrocytomas and 14 rhabdomyosarcomas (7 each of embryonal and alveolar types). LOH of chromosome 22 markers is known to occur in meningioma, malignant melanoma, breast cancer, and ependymoma. SSCP of all 17 exons of the NF2 gene in 27 melanoma cell lines, 42 breast cancers, and 27 pendymomas revealed no alterations. In a screen of 151 menigiomas, 26 new variants have been found, bringing our total to 50 variants in this sample. These represent inactivating mutations (frameshift, splice-site, and nonsense), determined by direct sequencing. Since the majority of these changes occur in tumors previously shown to have LOH at chromosome 22 markers flanking NF2, our results support a tumor sequence role for this gene in meningiomas. In addition, given that 40% of our tumors do not show LOH over this region, we propose that other genes are involved in the development of this latter subset of meningiomas.

  20. Loss of neurofibromatosis type 1 (NF1) gene expression in pheochromocytomas from patients without NF1

    SciTech Connect

    Geist, R.T.; Gutmann, D.H.; Moley, J.F.

    1994-09-01

    The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, termed neurofibromin. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 as well as malignant and neuroblastomas from patients without NF1. Previously, we demonstrated the lack of neurofibromin expression in six pheochromocytomas from patients with NF1, suggesting that neurofibromin loss is associated with the progression to neoplasia in pheochromocytomas in these patients. The lack of NF1 gene expression in NF1 patient pheochromocytomas supports the notion that neurofibromin might be an essential regulator of cell growth in these cells. To determine whether NF1 gene expression is similarly altered in pheochromocytomas from patients without NF1, twenty pheochromocytomas were examined for the presence of NF1 RNA by reverse-transcribed PCR (RT-PCR). Lack of NF1 gene expression was documented in four of these twenty tumors (20%) which corresponds to previously reported numbers for malignant melanomas and neuroblastomas in non-NF1 patients. Of these twenty pheochromocytomas, one of four sporadic tumors, one of ten tumors from patients with MEN2A, one of four tumors from patients with MEN2B, and one of two tumors from patients with von Hippel-Lindau syndrome demonstrated loss of NF1 gene expression. In all cases, the quality and quantity of tumor RNA was determined by RT-PCR amplification using primers which amplify cyclophilin RNA. We previously demonstrated that these tumors do not harbor activating mutations of the N-ras, K-ras or H-ras proto-oncogenes. These results suggest that loss of NF1 gene expression is frequently associated with the progression to neoplasia in tumors derived from adrenal medullary tissue in patients without clinical manifestations of neurofibromatosis and supports the notion that neurofibromin is a tumor suppressor gene product involved in the pathogenesis of a wide variety of tumor types.

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

    SciTech Connect

    Norton, K.K.; Dowton, B.; Silow-Santiago, I.

    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.

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

    PubMed

    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).

  3. Incidental parenchymal magnetic resonance imaging findings in the brains of patients with neurofibromatosis type 2☆

    PubMed Central

    Vargas, Wendy S.; Heier, Linda A.; Rodriguez, Fausto; Bergner, Amanda; Yohay, Kaleb

    2014-01-01

    Purpose Whereas T2 hyperintensities known as NF-associated bright spots are well described in patients with neurofibromatosis type I (NF-1), there is a paucity of data on incidental findings in patients with neurofibromatosis type II (NF-2). We aim to characterize unexplained imaging findings in the brains of patients with NF-2. Materials and methods This study is retrospective, HIPAA-compliant and approved by the institutional review board. 34 patients with NF-2 underwent brain magnetic resonance imaging (MRI) between January 2000 and December 2012. T2 and T1-weighted imaging characteristics, diffusion weighted imaging (DWI) characteristics, and enhancement patterns were analyzed by visual inspection. Clinical information at time of imaging was available for all patients. Neuropathologic data was available for one patient. Results We found unexplained T2 hyperintensities present on initial imaging in 23/34 patients (67%). Of the 23 patients with unexplained MRI findings, 15 (65%) had wedge-shaped T2 hyperintensities in the subcortical white matter extending to the cortex suggestive of a cortical dysplasia. 3 additional cases (17%) had a lesion within the cerebellum suggestive of a neuronal migration anomaly. In one patient where the MRI was suggestive of focal cortical dysplasia, histopathologic analysis revealed dysplastic glial foci without other alterations of cortical architecture or other cytologic abnormalities. Conclusion Unexplained T2 hyperintensities occur frequently in patients with NF-2. While they may not be the NF-2 equivalent of NF-associated bright spots seen in NF-1, some of these T2 hyperintensities in patients with NF-2 may represent underlying disorders of neuronal migration. Further studies are needed to validate our findings. PMID:24501699

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

    PubMed

    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.

  5. Coexistence of multiple rare spinal abnormalities in type 1 neurofibromatosis: a case report and literature review

    PubMed Central

    Zhao, Chun-Ming; Zhang, Wen-Jie; Huang, Ai-Bing; Chen, Qian; He, Yuan-Long; Zhang, Wei; Yang, Hui-Lin

    2015-01-01

    Orthopaedic involvement is the most common clinical presentation of Neurofibromatosis type 1 (NF-1) patients with the spinal abnormalities more frequently affected. In the spinal deformities of NF-1 patients, despite the scoliosis is the most frequent finding, several distinctive radiographic features, such as dural ectasia, defective pedicles, and spondylolisthesis, are relatively less common. Here, we reported a 16-year-old boy diagnosed with NF-1 who presented with dural ectasia, defective pedicles, and spondylolisthesis concomitantly, described the surgical treatment and provided a literature review. The boy complained of low back and leg pain for two months. On clinical examination, the patient showed multiple café au lait spots on his back and no neurological deficit. He had a family history of neurofibromatosis as his father suffering from NF-1. Imaging results demonstrated mild scoliosis, posterior scalloping of the lumber spine, L5 spondylolisthesis on plain radiographs, and marked dural ectasia of L3-L5 on MRI. Furthermore, the CT scan showed presence of thin pedicles at L3, bilateral symmetrical pedicle clefts at L4, and pars interarticularis fractures at L5. The patient received a long level posterior fusion from L1 to S1 with pedicle screws. Iliac crest autogenous graft mixed with artificial bone were used to achieve solid arthrodesis. At nine-month follow-up, the patient was asymptomatic and able to live a normal life. Our observation demonstrated that familiarity with those distinctive features in NF-1 patients could be contributed to making an early diagnosis and optimizing treatment. PMID:26770321

  6. Recurrent Diffuse Neurofibroma of Nose Associated with Neurofibromatosis Type 1: A Rare Case Report with Review of Literature

    PubMed Central

    Chander, Vimal; Rao, RVM Surya; Sekhar, Ganthimathy; Raja, Alagar; Sridevi, M

    2015-01-01

    Diffuse neurofibroma is an unusual variant of neurofibroma with the head and neck being the common sites of involvement. It is benign in nature and spreads superficially and has many ectatic blood vessels. Histologically it is similar to conventional neurofibromas except for a few peculiar distinguishing features. We report a case of a 14-year-old boy who presented with a diffuse recurrent painless swelling over the dorsum of the nose with the clinical stigmata of neurofibromatosis. Microscopy revealed a diagnosis of diffuse neurofibroma with a few foci showing differentiation towards Meissner's type of tactile corpuscles. It is important to recognize this entity as it has a tendency to recur, yet hardly ever become malignant and is almost always associated with neurofibromatosis type 1. PMID:26677270

  7. Cherubism associated with neurofibromatosis type 1, and multiple osteolytic lesions of both femurs: a previously undescribed association of findings.

    PubMed

    Martínez-Tello, Francisco J; Manjón-Luengo, Palmira; Martin-Pérez, Manuel; Montes-Moreno, Santiago

    2005-12-01

    We present a patient with neurofibromatosis type 1, with the clinical, radiological and histological features of cherubism mandibular lesions, and multiple osteolytic, geographic lesions in both femurs, consistent with multiple non-ossifying fibromas. We have been unable to find a similar case in the world literature. We discuss our findings in relationship with a number of syndromes that present clinical, radiological or pathological similarities.

  8. Isolated huge aneurysm of the left main coronary artery in a 22-year-old patient with type 1 neurofibromatosis.

    PubMed

    Pontailler, Margaux; Vilarem, Didier; Paul, Jean-François; Deleuze, Philippe H

    2015-03-01

    A 22-year-old patient with neurofibromatosis type 1 presented with acute chest pain. A computed tomography scan and coronary angiography revealed a partially thrombosed huge aneurysm of the left main coronary artery. Despite medical treatment, the patient's angina recurred. The patient underwent a coronary bypass grafting operation and surgical exclusion of the aneurysm. Postoperative imaging disclosed good permeability of the 3 coronary artery bypass grafts and complete thrombosis of the excluded aneurysm.

  9. Revascularization in a 17-Year-Old Girl with Neurofibromatosis and Severe Hypertension Caused by Renal Artery Stenosis

    PubMed Central

    Geavlete, Oliviana D.; Botezatu, Simona; Postu, Marin; Popescu, Bogdan A.; Ginghina, Carmen; Coman, Ioan M.

    2017-01-01

    Renal artery stenosis caused by neurofibromatosis is a rare cause of renovascular hypertension. This hypertension can develop during childhood and is one of the leading causes of poor outcome. We report the case of a 17-year-old girl who was incidentally diagnosed with severe hypertension. During her examination for secondary hypertension, we reached a diagnosis of neurofibromatosis type 1 on the basis of a cluster of typical findings: optic nerve glioma, café au lait spots, nodular neurofibromas, and axillary freckling. Renal angiograms revealed a hemodynamically significant left renal artery stenosis (70%). Renal angioplasty with a self-expanding stent was performed one month later for rapidly progressive renal artery stenosis (90%) and uncontrolled blood pressure. Excellent blood pressure control resulted immediately and was maintained as of the 2-year follow-up evaluation. We think that percutaneous transluminal renal angioplasty can be effective in select patients who have neurofibromatosis type 1 and refractory hypertension caused by renal artery stenosis. PMID:28265213

  10. The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study.

    PubMed

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

    2014-10-01

    NF1, NF2, and Schwannomatosis are incurable tumor suppressor syndromes associated with poor quality of life. The aim of this study was to determine the feasibility, acceptability, and preliminary efficacy of an NF adapted, 8-week group mind body skills based intervention, the relaxation response resiliency program (3RP) aimed at improving resiliency and increasing satisfaction with life. Patients seen at MGH's Neurofibromatosis Clinic were offered participation if they described difficulties coping to a treating physician. Participants completed measures of life satisfaction, resiliency, stress, mood, lifestyle, pain, post-traumatic growth and mindfulness at baseline and after completing the 3RP program. The intervention had relative feasible enrollment rate (48% rate, 32 out of 67 of patients signing the informed consent form). However, out of the 32 patients who signed the informed consent, only 20 started the study (62.5%) and only 16 completed it (50%), suggesting problems with feasibility. The main reason cited for non-participation was burden of travel to the clinic. The intervention was highly acceptable, as evidenced by an 80% completion rate (16/20). Paired t tests showed significant improvement in resiliency, satisfaction with life, depression, stress, anxiety, mindfulness and post traumatic growth, with effect sizes ranging from 0.73-1.33. There was a trend for significance for improvement in somatization and sleepiness (p = 0.06), with effect sizes of 0.54-0.92 respectively. Statistically nonsignificant improvement was observed in all other measures, with effect sizes small to medium. In sum, the 3RP was found to be relatively feasible, highly acceptable and preliminary efficacious in decreasing symptom burden in this population, supporting the need of a randomized controlled trial.

  11. Neurofibromatosis-1

    MedlinePlus

    ... the same NF1 gene change. "Coffee-with-milk" ( café-au-lait ) spots are the hallmark symptom of ... Many healthy people have one or two small café au lait spots. However, adults who have six ...

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

    PubMed Central

    2011-01-01

    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 International Classification of

  13. Tratamiento Quirúrgico de los Meningiomas del Foramen Óptico, Técnicay Resultados de una Serie de 18 Pacientes

    PubMed Central

    Goldschmidt, Ezequiel; Ajler, Pablo; Campero, Álvaro; Landriel, Federico; Sposito, Maximiliano; Carrizo, Antonio

    2014-01-01

    Introducción: los meningiomas del foramen óptico producen un rápido deterioro de la función visual aún cuando su tamaño es pequeño, por eso su diagnóstico y manejo difiere del resto de los meningiomas clinoideos. El propósito de este estudio es presentar la técnica y los resultados de nuestro manejo quirúrgico de meningiomas foraminales (MF). Pacientes y Métodos: se llevó a cabo una revisión de las historias clínicas de 47 pacientes con meningiomas primarios intraorbitarios. Se realizaron 52 cirugías en los pacientes con MF. Se empleó una craneotomía fronto-orbitaria, seguida de una descompresión extradural del canal óptico, resección del componente intraorbitario y exploración intradural del nervio óptico. Resultados: de los 12 pacientes con MF que presentaban la visión conservada, la agudeza visual fue preservada en 7 casos, mejoró en 2, y empeoró en 3. En 18 pacientes, el principal síntoma fue exoftalmos y en 35 pacientes ceguera unilateral. Ocurrieron 6 recurrencias, 2 a 10 años después de la resección quirúrgica. Cinco de ellos fueron reoperados. Se indicó radioterapia después de la recurrencia en 3 pacientes. Conclusión: el manejo de los MF continúa siendo controvertido y frecuentemente se propone un tratamiento conservador. Basados en nuestros hallazgos de frecuente extensión intracraneal, proponemos realizar una resección total o subtotal del tumor, preservando el nervio óptico en pacientes con visión prequirúrgica conservada. PMID:25165616

  14. Spinal Cord Ependymoma Associated with Neurofibromatosis 1 : Case Report and Review of the Literature

    PubMed Central

    Shan, Ming; Feng, Chunguo; Wang, Xiaojie

    2014-01-01

    Patients with neurofibromatosis 1 (NF1) are predisposed to develop central nervous system tumors, due to the loss of neurofibromin, an inactivator of proto-oncogene Ras. However, to our knowledge, only three cases of ependymomas with NF1 have been reported in the literature. The authors present a case of NF1 patient with a spinal cord ependymoma. She was referred for about half a year history of increasing numbness that progressed from her fingers to her entire body above the bellybutton. Magnetic resonance imaging revealed a relative-demarcated, heterogeneously enhanced mass lesion accompanied by perifocal edema in C5-7 level, a left-sided T11 spinous process heterogeneously enhanced mass in soft tissue, intervertebral disk hernia in L2-5 level, and widespread punctum enhancing lesion in her scalp and in T11-L5 level. The patient underwent C5-7 laminectomies and total excision of the tumor under operative microscope, and intraoperative ultrasonography and physiological monitoring were used during the surgery. Histopathologically, her tumor was found to be a ependymoma without malignant features (grade II in the World Health Organization classification). Therefore, no adjuvant therapy was applied. Following the operation, the patient showed an uneventful clinical recovery with no evidence of tumor recurrence after one year of follow-up. PMID:24570818

  15. Medical treatment in neurofibromatosis type 2. Review of the literature and presentation of clinical reports.

    PubMed

    Goutagny, S; Kalamarides, M

    2017-02-02

    The understanding of the molecular pathways underlying tumor development in neurofibromatosis type 2 (NF2) is increasing. Thus, repositioning drugs, drug therapies that are already clinically available for various cancers, appear potentially promising for NF2 patients. Based on preclinical data from in vitro or animal models, five different treatments have been proposed for selected NF2 cases. Evaluation of bevacizumab, a monoclonal antibody against VEGF has mainly been reported in retrospective studies; it has been reported to induce hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas (VS). In our experience with 16 patients, bevacizumab is associated with an increase of median time to tumor progression of VS from 5.6 months before bevacizumab onset, to more than 29.3 months. The need for intravenous injections and long term adverse events (hypertension, proteinuria, hemorrhage) are the main drawbacks. Lapatinib seemed promising in a single phase II trial with a volumetric response observed in 4/17 patients and a hearing response in 4/13, but is not currently used in clinical practice. Erlotinib has not been associated with radiographic or hearing responses in a phase II trial. Everolimus has been evaluated in 3 phase II trials. Everolimus did not induced tumor shrinkage, but seems to be able to increase time to tumor progression in selected cases. Currently, bevacizumab is the only drug proposed to selected NF2 patients.

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

    PubMed Central

    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

  17. Evidence of Increased Bone Resorption in Neurofibromatosis Type 1 Using Urinary Pyridinium Crosslink Analysis

    PubMed Central

    STEVENSON, DAVID A.; SCHWARZ, ELISABETH L.; VISKOCHIL, DAVID H.; MOYER-MILEUR, LAURIE J.; MURRAY, MARY; FIRTH, SEAN D.; D’ASTOUS, JACQUES L.; CAREY, JOHN C.; PASQUALI, MARZIA

    2011-01-01

    Although neurofibromatosis type 1 (NF1) is a neuro-cutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5–19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects. PMID:18317233

  18. Retrolabyrinthine approach for cochlear nerve preservation in neurofibromatosis type 2 and simultaneous cochlear implantation

    PubMed Central

    Bento, Ricardo Ferreira; Monteiro, Tatiana Alves; Bittencourt, Aline Gomes; Goffi-Gomez, Maria Valeria Schmidt; de Brito, Rubens

    2013-01-01

    Summary Introduction: Few cases of cochlear implantation (CI) in neurofibromatosis type 2 (NF2) patients had been reported in the literature. The approaches described were translabyrinthine, retrosigmoid or middle cranial fossa. Objectives: To describe a case of a NF2- deafened-patient who underwent to vestibular schwannoma resection via RLA with cochlear nerve preservation and CI through the round window, at the same surgical time. Resumed Report: A 36-year-old woman with severe bilateral hearing loss due to NF2 was submitted to vestibular schwannoma resection and simultaneous CI. Functional assessment of cochlear nerve was performed by electrical promontory stimulation. Complete tumor removal was accomplishment via RLA with anatomic and functional cochlear and facial nerve preservation. Cochlear electrode array was partially inserted via round window. Sound field hearing threshold improvement was achieved. Mean tonal threshold was 46.2 dB HL. The patient could only detect environmental sounds and human voice but cannot discriminate vowels, words nor do sentences at 2 years of follow-up. Conclusion: Cochlear implantation is a feasible auditory restoration option in NF2 when cochlear anatomic and functional nerve preservation is achieved. The RLA is adequate for this purpose and features as an option for hearing preservation in NF2 patients. PMID:25992034

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

    PubMed

    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.

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

    PubMed Central

    Miguel, Carmen Sílvia; Chaim-Avancini, Tiffany M; Silva, Maria Aparecida; Louzã, Mario Rodrigues

    2015-01-01

    Background 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. PMID:25848279

  1. Neurofibromatosis: an update of ophthalmic characteristics and applications of optical coherence tomography

    PubMed Central

    Abdolrahimzadeh, Barmak; Piraino, Domenica Carmen; Albanese, Giorgio; Cruciani, Filippo; Rahimi, Siavash

    2016-01-01

    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. PMID:27257370

  2. Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report

    PubMed Central

    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

  3. Neurofibromatosis type I (NFI) in Israeli families: Linkage analysis as a diagnostic tool

    SciTech Connect

    Elyakim, S.; Lerer, I.; Zlotogora, J.; Sagi, M.; Merin, S.; Abeliovich, D.; Gelman-Kohan, Z.

    1994-12-01

    Linkage analysis of 18 neurofibromatosis type I (NFI) families was performed using intragenic and flanking polymorphic markers. The aims of the analysis were prenatal diagnosis of at-risk fetuses, and of asymptomatic individuals who were relatives of NFI patients. Prenatal diagnosis was performed in 9 pregnancies of 7 families; 5 fetuses were diagnosed as affected. In 6 families with an affected spouse, the request was to identify informative polymorphisms to be used in future pregnancies. Presymptomatic diagnosis was performed in 4 families. One individual, a brother of an NFI patient, was found to have Lisch nodules as the only NFI symptom. Linkage analysis indicated that if this person is a carrier of the NFI gene, he must be a product of intragenic crossover. In 2 individuals with a new NFI mutation, the origin of the NFI-bearing chromosomes was paternal. The same observation was noted by others. A summary of published cases shows that some 90% of the NFI-bearing chromosomes of patients with new mutations were of paternal origin. We therefore suggest that for the purpose of prenatal diagnosis in carriers of NFI new (and unidentified) mutations, the paternal chromosome will be considered as the NFI-bearing chromosome. 49 refs., 4 figs., 3 tabs.

  4. Genetic and physical map of the von Recklinghausen neurofibromatosis (NF1) region on chromosome 17

    SciTech Connect

    Yagle, M.K.; Parruti, G.; Xu, W.; Solomon, E. ); Ponder, B.A.J. )

    1990-09-01

    The von Recklinghausen neurofibromatosis 1 (NF1) locus has been previously assigned to the proximal long arm of chromosome 17, and two NF1 patients have been identified who have constitutional balanced translocations involving 17q11.2. The authors have constructed a cosmid library from a chromosome-mediated gene transfectant, KLT8, that contains approximately 10% of chromosome 17, including 17q11.2. Cosmids isolated from this library have been mapped across a panel of somatic cell hybrids, including the hybrids from the two patients, and have been localized to seven small regions of proximal 17q. They have 5 cosmids that map directly above the two NF1 translocations, and 11 cosmids that map directly below. Of these, 2 cosmids in each region are linked to the disease locus and 3 of these cosmids show no recombination. One distal cosmid, 2B/B35, detects the two NF1 translocations by pulsed-field gel analysis and has been used to produce a long-range restriction map that covers the translocations.

  5. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study.

    PubMed Central

    Stiller, C. A.; Chessells, J. M.; Fitchett, M.

    1994-01-01

    There is a well-known raised risk of leukaemia in children with neurofibromatosis type 1 (NF-1). We carried out the first detailed population-based study of leukaemia and non-Hodgkin lymphoma (NHL) associated with NF-1 in order to estimate the risk and elucidate the relationship between these conditions. Over the 17 year study period there were five cases of chronic myelomonocytic leukaemia (CMML) in patients with NF-1 (relative risk 221; 95% CI 71-514), 12 cases of acute lymphoblastic leukaemia (ALL) (relative risk 5.4; 95% CI 2.8-9.4) and five cases of NHL (relative risk 10.0; 95% CI 3.3-23.4). Marrow cytogenetics could be reviewed for seven patients. Specific abnormalities found were monosomy 21 in a child with CMML and 7p+, 17p- in a child with ALL. No abnormalities were reported of 17q, which includes the NF1 gene. CMML occurred predominantly in boys, who also had a family history of NF-1. ALL and NHL were more often found in children with no previous family history. PMID:7947106

  6. Fatal Retroperitoneal Bleeding Caused by Neurofibromatosis: A Case Report and Review of the Literature

    PubMed Central

    Moerbeek, Patrick R.; van Buijtenen, Jesse M.; van den Heuvel, Baukje; Hoksbergen, Arjan W. J.

    2015-01-01

    A young female was brought into the emergency department with pulseless electrical activity (PEA) after local resection of neurofibromateous lesions. Chest ultrasonography was normal. Abdominal ultrasonography was not performed. After successful resuscitation a total body CT-scan was performed to rule out potential bleeding sources. However, haemodynamic instability reoccurred and the scan had to be aborted at the thoracoabdominal level. No thoracic abnormalities were found. Resuscitation was reinitiated and abdominal ultrasonography was performed, showing a large amount of abdominal fluid. A progressive fall in haemoglobin was noted. Emergency laparotomy was performed, revealing a large retroperitoneal haematoma. Despite ligation and packing, bleeding continued. Postoperative angiography showed active bleeding from a branch of the left internal iliac artery, which could be successfully coiled. Unfortunately, the patient died five days later due to irreversible brain damage. Revision of an MRI scan made one year earlier showed a 10 cm large retroperitoneal neurofibromatous lesion exactly at the location of the current bleeding. This case shows that patients with neurofibromatosis might develop spontaneous life-threatening bleeding from retroperitoneal located lesions. Furthermore, it points out the necessity of focused assessment with ultrasonography of the abdomen in all patients with PEA of unknown origin. PMID:25688270

  7. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II. Guidelines for genetic counselling.

    PubMed Central

    Huson, S M; Compston, D A; Harper, P S

    1989-01-01

    The age of appearance and diagnostic value of the major defining features of von Recklinghausen neurofibromatosis (NF-1) have been studied in 168 cases from 73 families. In assessing children of an affected patient, those who have inherited the gene can be distinguished from their normal sibs on the basis of whether or not café au lait (CAL) spots are present by the age of five years. Lisch nodules appear before cutaneous neurofibromas and are a useful clinical aid in the assessment of unusual cases, those in whom the diagnosis is equivocal, and children with multiple CAL spots but no family history of NF-1. Sixty-nine of the families were identified through a population based study in south east Wales and the frequency of complications in 135 affected subjects from these families has been used to develop figures for genetic counselling. For these purposes, the complications of NF-1 can be usefully divided into four categories: intellectual handicap (33%) (moderate/severe retardation 3.2%, minimal retardation/learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity (8.5%); 'treatable' complications which can develop at any age (15.7%); and malignant or CNS tumours (4.4 to 5.2%). Images PMID:2511319

  8. Reconstruction of skull base defects in sphenoid wing dysplasia associated with neurofibromatosis I with titanium mesh.

    PubMed

    Lotfy, Mohamed; Xu, Risheng; McGirt, Matthew; Sakr, Sameh; Ayoub, Basim; Bydon, Ali

    2010-12-01

    Sphenoid wing dysplasia occurs in 3-7% of patients with neurofibromatosis type 1 (NF1). The typical radiological features are partial or complete absence of the greater wing of the sphenoid. This condition is slowly progressive and may result in temporal lobe herniation into the orbital cavity, producing pulsating exophthalmos and gross facial deformity. Thus, reconstruction of the orbit is important for both cosmetic and functional reasons. Traditional surgical treatment of sphenoid dysplasia involves split bone grafting and repair of the anterior skull base defect. However, several reports have demonstrated complications of graft resorption and recurrence of proptosis and pulsating exopthalmos. In this case series, we present two patients suffering from pulsating exophthalmos due to sphenoid dysplasia. Radiological and MRI studies demonstrated orbital enlargement and complete absence of the greater wing of the sphenoid. Surgical management of these patients involved dural defect repair, and the use of titanium mesh in conjunction with bone graft to act as a barrier between the orbit and the middle cranial fossa. The mesh was fixed by fine screws. Proptosis improved markedly post-operatively and resolved within a few weeks. Ocular pulsation subsided and remained quiescent with at least 1-year follow-up.

  9. Radiofrequency Ablation and Excision of Multiple Cutaneous Lesions in Neurofibromatosis Type 1

    PubMed Central

    Kim, Seong-Hun; Lee, Nae-Ho; Yang, Kyung-Moo

    2013-01-01

    Background Von Recklinghausen disease or neurofibromatosis type 1 is an autosomal dominant genetic disorder of chromosome 17q11.2. The most common characteristic findings of NF 1 include multiple and recurrent cutaneous neurofibromas associated with psychosocial distress. Methods Sixteen patients (9 female, 7 male; average age, 31 years; range, 16 to 67 years) with multiple cutaneous neurofibromas between March 2010 and February 2012 were included in the study. All patients were treated with radiosurgical ablation and excision under general anesthesia. Results All 16 patients were satisfied with the results, when questioned directly during the outpatient department follow-up. The only complaint from a few patients was minimal scarring, but acceptable results were obtained in the end. Conclusions The radiofrequency procedure is almost bloodless and quick, creating a smaller necrotizing zone. Therefore, instead of employing the time consuming traditional surgery, such as laser therapy and electrosurgical excision, that produces uncertain results and can affect normal adjacent tissue, treatment of neurofibromas with radiofrequency ablation and excision can be an alternative choice of treatment for patients with a large number of neurofibromas. PMID:23362481

  10. Neurofibromatosis type 1 with external genitalia involvement presentation of 4 patients.

    PubMed

    Pascual-Castroviejo, Ignacio; Lopez-Pereira, Pedro; Savasta, Salvatore; Lopez-Gutierrez, Juan Carlos; Lago, Carlos Míguelez; Cisternino, Mariangela

    2008-11-01

    Genitourinary neurofibromas with clitoral involvement in neurofibromatosis type 1 are rare, and even more infrequent are the neurofibromas involving genitalia in males. The most frequent presenting sign of neurofibroma in females is clitoromegaly with pseudopenis, and enlarged penis is the most common sign in males. Labium majus neurofibroma not associated with clitoral involvement is extremely rare. Magnetic resonance imaging demonstration of the neurofibromas has seldom been reported. We report 4 children, 3 girls and 1 boy, with plexiform neurofibromas involving the external genitalia. Three of the 4 patients had histologic confirmation of neurofibroma. Two girls with clitoral hypertrophy had a neurofibroma that infiltrated the clitoris and extended unilaterally to the lower bladder wall. One girl had a plexiform neurofibroma that affected a labium. One boy with asymmetric penile hypertrophy since 2 years of age and ipsilateral gluteal hypertrophy had plexiform neurofibromas that extended between the left lumbogluteal and penile regions, infiltrating the left rectum wall and bladder with compression of both structures, the left prostate, and the left half of the cavernous corpi with hypertrophy of this part and asymmetry of the penis. Magnetic resonance imaging demonstrated in all patients that external genitalia and plexiform neurofibroma formed images of nondetachable structures. However, hermaphroditism was discarded by chromosomal study in all 3 girls before ratifying the diagnosis of external genitalia neurofibroma.

  11. Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I

    SciTech Connect

    Metheny, L.J.; Amedeo, M.S.; Cappione, J.

    1995-11-01

    Neurofibromatosis type I (NF1) is a common genetic disease which leads to a variety of clinical features affecting cells of neural crest origin. In the period since the NF1 gene was isolated 1991, our understanding of the genetics of NF1 has increased remarkably. One of the most striking aspects of NF1 genetics is its complexity, both in terms of gene organization and expression. The gene is large and, when mutated, gives rise to diverse manifestations. A growing body of data suggests that mutations in the NF1 gene alone may not be responsible for all of the features of this disease. Epigenetic mechanisms, those which affect the NF1 transcript, play a role in the normal expression of the NF1 gene. Therefore, aberrations in those epigenetic processes are most likely pathogenic. Herein we summarize salient aspects of the vast body of NF1 literature and provide some insights into the myriad of regulatory mechanisms that may go awry in the genesis of this common but complex disease. 58 refs., 3 figs.

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

    PubMed Central

    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

  13. Resting state functional MRI reveals abnormal network connectivity in Neurofibromatosis 1

    PubMed Central

    Tomson, S.N.; Schreiner, M.; Narayan, M.; Rosser, Tena; Enrique, Nicole; Silva, Alcino J.; Allen, G.I.; Bookheimer, S.Y.; Bearden, C.E.

    2015-01-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits and autism spectrum disorders. As a single gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity MRI (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. PMID:26304096

  14. Screening for germline mutations in the neurofibromatosis type 2 (NF2) gene in NF2 patients

    SciTech Connect

    Andermann, A.A.; Ruttledge, M.H.; Rangaratnam, A.

    1994-09-01

    Neurofibromatosis type 2 (NF2) is an autosomal dominant disease with over 95% penetrance which predisposes gene carriers to develop multiple tumors of the central nervous system. The NF2 gene is a putative tumor suppressor gene which was previously mapped to the long arm of chromosome 22, and has recently been identified, using positional cloning techniques. The gene encodes a protein, schwannomin (SCH), which is highly homologous to the band 4.1 protein family. In an attempt to identify and characterize mutations which lead to the manifestation of the disease, we have used single strand conformation analysis (SSCA) to screen for germline mutations in all 17 exons of the NF2 gene in 59 unrelated NF2 patients, representing both familial and new mutations. A total of 27 migration abnormalities was found in 26 patients. Using direct sequencing analysis, the majority of these variants were found to result in nonsense, splice-site or frameshift mutations. Mutations identified in familial NF2 patients segregate in the family, and may prove to be useful tools for a simple and direct SSCA-based technique of presymptomatic or prenatal diagnosis in relatives of patients with NF2. This may be of particular importance in children of patients who have new mutations in the NF2 gene, where linkage analysis may not be feasible.

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

    PubMed Central

    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

  16. An analysis of variation in expression of neurofibromatosis (NF) type I (NFI): Evidence for modifying genes

    SciTech Connect

    Easton, D.F.; Ponder, B.A.J. ); Huson, S.M. ); Ponder, M.A. )

    1993-08-01

    Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component, the authors examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored - number of cafe-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored - the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For cafe-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiformneurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. The authors conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other [open quotes]modifying[close quotes] loci and that these modifying genes are trait specific. 22 refs., 8 tabs.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  3. Language in young children with neurofibromatosis-1: relations to functional communication, attention, and social functioning.

    PubMed

    Brei, Natalie G; Klein-Tasman, Bonita P; Schwarz, G Nathanael; Casnar, Christina L

    2014-10-01

    In this study, the language abilities of 30 children with Neurofibromatosis Type 1 (NF1) aged 4-6 years were examined using a standardized measure of language. Relations of language to multiple parental report measures of functional communication, social skills, and attention problems were investigated. Difficulties in core language skills were observed, and more than 1/3 of the children struggled on at least one language index. Language abilities were significantly related to parental report of functional communication, social interaction and communication, and social skills, such that language difficulties may be a risk factor for communication and social interaction challenges and communication-related adaptive behavior in children with NF1. Though receptive language abilities were an area of particular difficulty for many children with NF1, they were not significantly related to parental ratings of social functioning and functional communication. Few significant relations were found between language and parent-reported attention problems, although some trends were noted. Hence attention difficulties in children with NF1 may contribute to, but do not appear to fully account for, language difficulties. In sum, there is an increased risk of language difficulties for young children with NF1, and lab-measured language difficulties appear to relate to everyday communication and social interaction functioning.

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

    PubMed

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

    2017-03-06

    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.

  5. Reproductive decisions after prenatal diagnosis in neurofibromatosis type 1: importance of genetic counseling.

    PubMed

    Terzi, Y K; Oguzkan-Balci, S; Anlar, B; Aysun, S; Guran, S; Ayter, S

    2009-01-01

    Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders affecting approximately 1/3500 individuals in all ethnic groups. It is characterized by cutaneous and plexiform neurofibromas, café-au-lait spots, Lisch nodules, freckling in axillary and inguinal regions, optic gliomas and an increased risk of malignancy. The mutation rate of NF1 is one of the highest known for human disorders: approximately 50% of all affected individuals carry de novo mutations. Detection of disease causing mutations in the NF1 gene allows presymptomatic and prenatal diagnosis, but is complex and time-consuming due to the large size of the gene, the existence of pseudogenes, the lack of clustering of the mutations in a particular region of the gene, and the variability of clinical findings. Because the time for investigations in prenatal diagnosis is restricted, detection of disease-associated NF1 alleles is more rapid and useful especially for familial cases. Therefore, genetic diagnosis of NF1 is frequently performed by linkage analysis. In our laboratory, 37 families were characterized with this method, of which two requested prenatal diagnosis. One fetus was found to be under NF1 risk. However, parents elected to continue pregnancy: the child is now 2.5 years old and has NF1 features. The phenotypic variability and the absence of genotype-phenotype correlation create difficulties in reproductive decisions for NF1 families, underlining the importance of appropriate counseling and detailed discussion of possible outcomes before genetic testing of the fetus.

  6. Synchronous multiple colonic adenocarcinomas arising in patient with neurofibromatosis type 1

    PubMed Central

    Kim, Ik Yong; Cho, Mee Yon

    2014-01-01

    We report a case of synchronous multiple colon adenocarcinomas in a patient with neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant inherited disorder and patients with NF1 have high risk for both benign and malignant tumors. However, adenocarcinomas involving the colon have rarely been reported in patients with NF1. A 61-year-old man was referred for generalized peritonitis due to descending colon perforation. Left hemicolectomy was performed and pathologic examination showed four adenocarcinomas. Peritoneal nodules were confirmed as metastatic adenocarcinoma (pT4N1M1). The patient also had clinical features compatible with NF1 such as café au lait macules, axillary freckles, neurofibromas across the body, and Lisch nodules. Upon review of the literature, colon adenocarcinoma in patients with NF1 tends to occur in males and relatively young age groups, and is associated with advanced tumor stages and multiple colon cancers. To improve treatment outcome, early colonoscopic surveillance should be considered in patients with NF1. PMID:25247170

  7. Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1.

    PubMed Central

    Tada, Kenji; Kochi, Masato; Saya, Hideyuki; Kuratsu, Jun-ichi; Shiraishi, Shoji; Kamiryo, Takanori; Shinojima, Naoki; Ushio, Yukitaka

    2003-01-01

    Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that predisposes sufferers to various forms of neoplasia. Among affected individuals, 15%-20% develop astrocytomas, especially pilocytic astrocytomas (PA), which are benign and classified as grade I by the World Health Organization. They are generally well circumscribed, and their progression is slow. NF1-associated PAs (NF1-PAs) occasionally behave as aggressive tumors. To elucidate underlying genetic events in clinically progressive NF1-PAs, we performed molecular genetic analysis on 12 PAs, including 3 NF1-PAs, for pS3, p16, and epidermal growth factor receptor genes, as well as loss of heterozygosity (LOH) on chromosome 1p, 10, 17, and 19q. None of the obvious genetic alterations typically seen in higher grade astrocytomas were found in 9 sporadic PAs. However, in 2 of 3 NF1-PAs, microsatellite analysis showed LOH10, including the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene locus, despite the diagnosis of pilocytic astrocytoma;one of these also manifested homozygous deletion of the p16 gene. The other NF1-PA harbored only LOH of the NF1 gene locus (17q). Our preliminary results support the hypothesis that some NF1-PAs differ genetically from sporadic PAs. PMID:14565158

  8. A murine model of neurofibromatosis type 2 that accurately phenocopies human schwannoma formation

    PubMed Central

    Gehlhausen, Jeffrey R.; Park, Su-Jung; Hickox, Ann E.; Shew, Matthew; Staser, Karl; Rhodes, Steven D.; Menon, Keshav; Lajiness, Jacquelyn D.; Mwanthi, Muithi; Yang, Xianlin; Yuan, Jin; Territo, Paul; Hutchins, Gary; Nalepa, Grzegorz; Yang, Feng-Chun; Conway, Simon J.; Heinz, Michael G.; Stemmer-Rachamimov, Anat; Yates, Charles W.; Wade Clapp, D.

    2015-01-01

    Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder resulting from germline mutations in the NF2 gene. Bilateral vestibular schwannomas, tumors on cranial nerve VIII, are pathognomonic for NF2 disease. Furthermore, schwannomas also commonly develop in other cranial nerves, dorsal root ganglia and peripheral nerves. These tumors are a major cause of morbidity and mortality, and medical therapies to treat them are limited. Animal models that accurately recapitulate the full anatomical spectrum of human NF2-related schwannomas, including the characteristic functional deficits in hearing and balance associated with cranial nerve VIII tumors, would allow systematic evaluation of experimental therapeutics prior to clinical use. Here, we present a genetically engineered NF2 mouse model generated through excision of the Nf2 gene driven by Cre expression under control of a tissue-restricted 3.9kbPeriostin promoter element. By 10 months of age, 100% of Postn-Cre; Nf2flox/flox mice develop spinal, peripheral and cranial nerve tumors histologically identical to human schwannomas. In addition, the development of cranial nerve VIII tumors correlates with functional impairments in hearing and balance, as measured by auditory brainstem response and vestibular testing. Overall, the Postn-Cre; Nf2flox/flox tumor model provides a novel tool for future mechanistic and therapeutic studies of NF2-associated schwannomas. PMID:25113746

  9. Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1.

    PubMed

    Tomson, Steffie N; Schreiner, Matthew J; Narayan, Manjari; Rosser, Tena; Enrique, Nicole; Silva, Alcino J; Allen, Genevera I; Bookheimer, Susan Y; Bearden, Carrie E

    2015-11-01

    Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

  10. Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes.

    PubMed

    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.

  11. A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1

    PubMed Central

    2012-01-01

    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. PMID:22824559

  12. Large Cervical Vagus Nerve Tumor in a Patient with Neurofibromatosis Type 1 Treated with Gross Total Resection: Case Report and Review of the Literature

    PubMed Central

    Bray, David P.; Chan, Andrew K.; Chin, Cynthia T.; Jacques, Line

    2016-01-01

    Neurofibromas are benign peripheral nerve sheath tumors that occur commonly in individuals with neurocutaneous disorders such as neurofibromatosis type 1. Vagal nerve neurofibromas, however, are a relatively rare occurrence. We present the case of a 22-year-old man with neurofibromatosis type 1 with a neurofibroma of the left cervical vagal nerve. The mass was resected through an anterior approach without major event. In the postoperative course, the patient developed left vocal cord paralysis treated with medialization with injectable gel. We then present a comprehensive review of the literature for surgical resection of vagal nerve neurofibromas. PMID:28077961

  13. Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study.

    PubMed Central

    Evans, D G; Mason, S; Huson, S M; Ponder, M; Harding, A E; Strachan, T

    1997-01-01

    OBJECTIVE: To delineate the clinical phenotype, molecular basis, and implications for screening in patients and families with multiple schwannomas not generally involving the cranium. METHODS: As part of a United Kingdom clinical and genetic study of type 2 neurofibromatosis (NF2) patients and families with multiple schwannomas who do not fulfil diagnostic criteria for NF2 have been identified. The clinical phenotype was studied in the extended families and molecular analysis was carried out at the NF2 gene locus on chromosome 22. RESULTS: Patterns of inheritance in five families with schwannomatosis are consistent with inheritance of an autosomal dominant gene. The consistency of phenotype, with relative sparing of the cranium, is constant in these families. However, families which initially seem to be indicative of schwannomatosis may develop into classic NF2 as shown by a sixth family. Many of the tumours found in these families were referred to as "neurofibroma" when they were clearly schwannomas. This difference in classification has major implications for the relative risk of each particular type of neurofibromatosis and neuropathological review may be important in some cases. Genetic linkage analysis in the two largest families is entirely consistent with primary involvement of the NF2 gene. CONCLUSIONS: Variant forms of neurofibromatosis have presented a dilemma in classification and determination of recurrence risks in families. Previous reports have suggested that schwannomatosis is a sporadic non-hereditary condition. Patients with multiple schwannomas are likely to have a variant form of NF2 and up to a 50% risk of passing on a gene predisposing to multiple schwannoma. Images PMID:9120449

  14. Giant malignant peripheral nerve sheath tumor of thigh in an adolescent with neurofibromatosis type 1: a case report

    PubMed Central

    Tosun, Hacı Bayram; Serbest, Sancar; Turk, Bilge Aydın; Gumustas, Seyit Ali; Uludag, Abuzer

    2015-01-01

    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. PMID:26604833

  15. Mechanical Ptosis in Neurofibromatosis Type 1 Heralding the Diagnosis of Right Sided Cervical Vagus Nerve Neurofibroma: A Rare Case Report

    PubMed Central

    Parija, Sucheta; Panda, Bijnya; Pujahari, Susanta; Jena, Satyaswarup

    2016-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder. In NF1, involvement of vagus nerve can occur in the form of neurofibroma. A few cases of neurofibroma of thoracic vagus nerve have been reported while neurofibroma of cervical vagus nerve with NF1 is quite rare. A 19-year-old male came with complaints of decreased vision of both eyes and right sided drooping of eyelid since childhood. He was diagnosed as having NF1 with neurofibroma of right cervical vagus nerve. PMID:27504321

  16. Whole Exome Sequencing of Growing and Non-Growing Cutaneous Neurofibromas from a Single Patient with Neurofibromatosis Type 1

    PubMed Central

    Faden, Daniel L.; Asthana, Saurabh; Tihan, Tarik; DeRisi, Joseph; Kliot, Michel

    2017-01-01

    The growth behaviors of cutaneous neurofibromas in patients with Neurofibromatosis type 1 are highly variable. The role of the germline NF1 mutation, somatic NF1 mutation and mutations at modifying loci, are poorly understood. We performed whole exome sequencing of three growing and three non-growing neurofibromas from a single individual to assess the role of acquired somatic mutations in neurofibroma growth behavior. 1–11 mutations were identified in each sample, including two deleterious NF1 mutations. No trends were present between the types of somatic mutations identified and growth behavior. Mutations in the HIPPO signaling pathway appeared to be overrepresented. PMID:28099461

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

    PubMed

    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.

  18. Pilot Phase II Trial of Imatinib Mesylate in Neurofibromatosis Type 1 patients with Plexiform Neurofibromas

    PubMed Central

    Robertson, Kent A.; Nalepa, Grzegorz; Yang, Feng-Chun; Bowers, Daniel C.; Ho, Chang Y.; Hutchins, Gary D.; Croop, James M.; Vik, Terry A.; Denne, Scott C.; Parada, Luis F.; Hingtgen, Cynthia M.; Walsh, Laurence E.; Yu, Menggang; Pradhan, Kamnesh R.; Edwards-Brown, Mary K.; Cohen, Mervyn D.; Fletcher, James W.; Travers, Jeffrey B.; Staser, Karl W.; Lee, Melissa W.; Sherman, Marcie R.; Davis, Cynthia J.; Miller, Lucy C.; Ingram, David A.; Clapp, D. Wade

    2016-01-01

    Summary BACKGROUND Plexiform neurofibromas (PN) are slow growing chemoradiotherapy resistant tumours arising in patients with neurofibromatosis type I (NF1). Currently there are no viable therapeutic options for patients whose life-threatening plexiform neurofibromas cannot be surgically removed due to proximity to vital body structures. Based on identification of molecular targets in genetic mouse models of human NF1 tumours, we hypothesized that the oral kinase inhibitor, imatinib mesylate, may be effective in targeted treatment of these chemoradiotherapy-refractory tumours. METHODS An open-label pilot Phase II clinical trial was designed to test whether treatment with imatinib mesylate can decrease volume burden of clinically significant plexiform neurofibromas in NF1 patients. The entry criteria require patients only to have NF1 and a clinically significant plexiform neurofibroma with the specified age limitations (age 3–65). Patients were treated with daily oral imatinib at 440 mg/m2/day for children and 800 mg/day for adults divided twice daily for 6 months. The primary endpoint measure of significant response was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data was analyzed on an intent to treat basis, however to determine the activity of imatinib on NF1-related plexiform tumours, patients able to take imatinib for 6 months were evaluated for their response. Secondary outcomes included evaluation of safety of imatinib mesylate in this group of patients. The trial is registered at http://clinicaltrials.gov/; study number 0512-25. The trial currently is closed to enrollment, however there is a single patient that continues to respond and remains on study. FINDINGS On an intent to treat basis, 6 out of 36 patients or 17% (95% CI: 6 – 33%) experienced objective response to imatinib mesylate. In the evaluable study population of patients (n=23) who received drug for at least six months, six patients (26%; 95% CI

  19. Brief Report: The Prevalence of Neurofibromatosis Type 1 among Children with Autism Spectrum Disorder Identified by the Autism and Developmental Disabilities Monitoring Network

    ERIC Educational Resources Information Center

    Bilder, Deborah A.; Bakian, Amanda V.; Stevenson, David A.; Carbone, Paul S.; Cunniff, Christopher; Goodman, Alyson B.; McMahon, William M.; Fisher, Nicole P.; Viskochil, David

    2016-01-01

    Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). The frequency of ASD/NF1 co-occurrence has been subject to debate since the 1980s. This relationship was investigated in a large population-based sample of 8-year-old children identified with…

  20. Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

    PubMed

    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

  1. [Neurofibromatosis type 1 - description of clinical features and molecular mechanism of the disease].

    PubMed

    Bikowska-Opalach, Barbara; Jackowska, Teresa

    2013-01-01

    Neurofibromatosis type 1 (NF1) called also von Recklinghausen's disease is an autosomal dominant genetic disorder with a  complex clinical course. Clinical signs and symptoms concern mainly skin (with pigmentation abnormalities- café au lait macules, axillary/groin freckling and neurofibromas) and central nervous system (cognitive impairment, epilepsy, attention deficit hyperactivity disorder and gliomas). However, pathologic changes may also affect other organs and systems, including skeletal system (scoliosis, hypostature, osteoporosis, pseudoarthrosis and sphenoid wing dysplasia) or cardiovascular system (hypertension, inherited cardiovascular malformations). Another characteristic abnormality, which is an important diagnostic criterion of the disease, is the presence of Lisch nodules- hamartomatic changes of the iris. The development of NF1 is a consequence of inactivation of NF1 gene. The gene, located on chromosome 17, has one of the greatest frequencies of spontaneous mutation in the whole human genome. Gene product, a cytoplasmic protein called neurofibromin, is a tumor suppressor, with expression detected in various cells, mainly in malanocytes, neurons, Schwann cells and glial cells. Due to its anti-tumoral function, inactivation of NF1 protein leads to the growth of several neoplasms, concerning mainly skin and central nervous system (CNS). Skin tumors are actually malignances of the peripheral nervous system (PNS) and include cutaneous, subcutaneous and plexiform neurofibromas. In the CNS the most frequently occurring tumors are gliomas located in the optic pathway, followed by those developing in other parts of CNS. Histologically, CNS tumors are usually a  benign pilocytic astrocytoma, consisting of malignant-transformed astrocytes.

  2. The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2.

    PubMed

    Morris, Katrina A; Afridi, Shazia K; Evans, D Gareth; Hensiek, Anke E; McCabe, Martin G; Kellett, Mark; Halliday, Dorothy; Pretorius, Pieter M; Parry, Allyson

    2016-12-16

    OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.

  3. Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort.

    PubMed

    Morris, Katrina A; Golding, John F; Blesing, Claire; Evans, D Gareth; Ferner, Rosalie E; Foweraker, Karen; Halliday, Dorothy; Jena, Raj; McBain, Catherine; McCabe, Martin G; Swampillai, Angela; Warner, Nicola; Wilson, Shaun; Parry, Allyson; Afridi, Shazia K

    2017-01-01

    Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11-66 years), were followed for a median of 32.7 months (range 12.0-60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24 %) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5 %) had proteinuria. Of 36 patients followed for 36 months, 78 % were free from hypertension and 86 % were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.

  4. Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I

    PubMed Central

    Huijbregts, Stephan C.J.; Veer, Ilya Milos; Swaab, Hanna S.; Van Buchem, Mark A.; Schmidt, Reinhold; Rombouts, Serge A.

    2015-01-01

    Abstract Neurofibromatosis type 1 (NF1) has regularly been associated with cognitive, social, and behavioral problems. The fact that many different cognitive and behavioral impairments have been observed in NF1 suggests that networks of brain regions are involved rather than specific brain regions. Here, we examined whether functional connectivity was different in NF1 and, if so, whether associations were present with cognitive, social, and behavioral outcomes. Fourteen NF1 patients (8 male, age: M=12.49, SD=2.65) and 30 healthy controls (HC; 23 male, age: M=12.30, SD=2.94; p=0.835) were included. Functional connectivity was assessed using functional resting-state scanning. We analyzed brain regions that have been associated with cognitive and social functions: the bilateral ventral anterior cingulate cortex (vACC), the bilateral amygdala, the bilateral orbitofrontal cortex (OFC), and the posterior cingulate cortex (PCC). For NF1 patients, connection strengths between brain regions showing HC-NF1 differences were correlated with parent reports of cognitive, social, and behavioral functioning. Compared to HC, patients showed differences in functional connectivity between the left vACC and the frontal cortex, insula, and subcortical areas (caudate, putamen), between the left amygdala and the frontal cortex, insula, supramarginal gyrus, and PCC/precuneus, and between the left OFC and frontal and subcortical areas (caudate, pallidum). In patients, indications were found for associations between increased frontofrontal and temporofrontal functional connectivity with cognitive, social, and behavioral deficits (r-range=0.536–0.851). NF1 patients showed differences in functional connectivity between areas associated with cognitive and social functioning when compared to controls. This, plus the fact that connectivity strengths in these networks were associated with worse cognitive, social, and behavioral outcomes, suggests a neuropathological basis for the widespread

  5. Evolution and Origin of HRS, a Protein Interacting with Merlin, the Neurofibromatosis 2 Gene Product

    PubMed Central

    Omelyanchuk, Leonid V.; Pertseva, Julia A.; Burns, Sarah S.; Chang, Long-Sheng

    2009-01-01

    Hepatocyte growth factor receptor tyrosine kinase substrate (HRS) is an endosomal protein required for trafficking receptor tyrosine kinases from the early endosome to the lysosome. HRS interacts with Merlin, the Neurofibromatosis 2 (NF2) gene product, and this interaction may be important for Merlin’s tumor suppressor activity. Understanding the evolution, origin, and structure of HRS may provide new insight into Merlin function. We show that HRS homologs are present across a wide range of Metazoa with the yeast Vps27 protein as their most distant ancestor. The phylogenetic tree of the HRS family coincides with species evolution and divergence, suggesting a unique function for HRS. Sequence alignment shows that various protein domains of HRS, including the VHS domain, the FYVE domain, the UIM domain, and the clathrin-binding domain, are conserved from yeast to multicellular organisms. The evolutionary transition from unicellular to multicellular organisms was accompanied by the appearance of a binding site for Merlin, which emerges in the early Metazoa after its separation from flatworms. In addition to the region responsible for growth suppression, the Merlin-binding and STAM-binding domains of HRS are conserved among multicellular organisms. The residue equivalent to tyrosine-377, which is phosphorylated in the human HRS protein, is highly conserved throughout the HRS family. Three additional conserved boxes lacking assigned functions are found in the HRS proteins of Metazoa. While boxes 1 and 3 may constitute the Eps-15-and Snx1-binding sites, respectively, box 2, containing the residue equivalent to tyrosine-377, is likely to be important for HRS phosphorylation. While several functional domains are conserved throughout the HRS family, the STAM-binding, Merlin-binding, and growth suppression domains evolved in the early Metazoa around the time the Merlin protein emerged. As these domains appear during the transition to multicellularity, their functional

  6. Analysis of chromosome 22 deletions in neurofibromatosis type 2-related tumors

    SciTech Connect

    Wolff, R.K.; Frazer, K.A.; Jackler, R.K.; Lanser, M.J.; Pitts, L.H.; Cox, D.R. )

    1992-09-01

    The neurofibromatosis type 2 (NF2) gene has been hypothesized to be a recessive tumor suppressor, with mutations at the same locus on chromosome 22 that lead to NF2 also leading to sporadic tumors of the types seen in NF2. Flanking markers for this gene have previously been defined as D22S1 centromeric and D22S28 telomeric. Identification of subregions of this interval that are consistently rearranged in the NF2-related tumors would aid in better defining the disease locus. To this end, the authors have compared tumor and constitutional DNAs, isolated from 39 unrelated patients with sporadic and NF2-associated acoustic neuromas, meningiomas, schwannomas, and ependymomas, at eight polymorphic loci on chromosome 22. Two of the tumors studied revealed loss-of-heterozygosity patterns, which is consistent with the presence of chromosome 22 terminal deletions. By using additional polymorphic markers, the terminal deletion breakpoint found in one of the tumors, an acoustic neuroma from an NF2 patient, was mapped within the previously defined NF2 region. The breakpoint occurred between the haplotyped markers D22S41/D22S46 and D22S56. This finding redefines the proximal flanking marker and localizes the NF2 gene between markers D22S41/D22S46 and D22S28. In addition, the authors identified a sporadic acoustic neuroma that reveals a loss-of-heterozygosity pattern consistent with mitotic recombination or deletion and reduplication, which are mechanisms not previously seen in studies of these tumors. This finding, while inconsistent with models of tumorigenesis that invoke single deletions and their gene-dosage effects, lends further support to the recessive tumor-suppressor model. 33 refs., 2 figs., 1 tab.

  7. Impairment of Procedural Learning and Motor Intracortical Inhibition in Neurofibromatosis Type 1 Patients

    PubMed Central

    Zimerman, Máximo; Wessel, Maximilian J.; Timmermann, Jan E.; Granström, Sofia; Gerloff, Christian; Mautner, Victor F.; Hummel, Friedhelm C.

    2015-01-01

    Background Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition? Methods We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls. Findings NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase. Interpretations Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as

  8. Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors

    SciTech Connect

    Wentworth, Stacy; Pinn, Melva; Bourland, J. Daniel; Guzman, Allan F. de; Ekstrand, Kenneth; Ellis, Thomas L.; Glazier, Steven S.; McMullen, Kevin P.; Munley, Michael; Stieber, Volker W.; Tatter, Stephen B.; Shaw, Edward G.

    2009-01-01

    Purpose: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. Methods and Materials: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. Results: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3-64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000-2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. Conclusions: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors.

  9. Deletions spanning the neurofibromatosis I gene: Identification and phenotype of five patients

    SciTech Connect

    Kayes, L.M.; Burke, W.; Bennett, R.; Ehrlich, P.; Stephens, K. ); Riccardi, V.M. ); Rubenstein, A. )

    1994-03-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by marked variation in clinical severity. To investigate the contribution to variability by genes either contiguous to or contained within the NF1 gene, the authors screened six NF1 patients with mild facial dysmorphology, mental retardation, and/or learning disabilities, for DNA rearrangement of the NF1 region. Five of the six patients had NF1 gene deletions on the basis of quantitative densitometry, locus hemizygosity, and analysis of somatic cell hybrid lines. Analysis of hybrid lines carrying each of the patient's chromosomes 17, with 15 regional DNA markers, demonstrated that each of the five patients carried a deletion >700 kb in size. Minimally, each of the deletions involved the entire 350-kb NF1 gene; the three genes - EVI2A, EVI2B, and OMG-that are contained within an NF1 intron; and considerable flanking DNA. For four of the patients, the deletions mapped to the same interval; the deletion in the fifth patient was larger, extending farther in both directions. The remaining NF1 allele presumably produced functional neurofibromin; no gene rearrangements were detected, and RNA-PCR demonstrated that it was transcribed. These data provide compelling evidence that the NF1 disorder results from haploid insufficiency of neurofibromin. Of the three documented de novo deletion cases, two involved the paternal NF1 allele and one the maternal allele. The parental origin of the single remaining expresses NF1 allele had no dramatic effect on patient phenotype. The deletion patients exhibited a variable number of physical anomalies that were not correlated with the extent of their deletion. All five patients with deletions were remarkable for exhibiting a large number of neurfibromas for their age, suggesting that deletion of an unknown gene in the NF1 region may affect tumor initiation or development. 69 refs., 5 figs., 1 tab.

  10. Germ-line mutations in the neurofibromatosis 2 gene: Correlations with disease severity and retinal abnormalities

    SciTech Connect

    Parry, D.M.; Kaiser-Kupfer, M.; Eldridge, R.

    1996-09-01

    Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P {le} .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study. 58 refs., 2 tabs.

  11. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1

    PubMed Central

    Sabbagh, Audrey; Pasmant, Eric; Laurendeau, Ingrid; Parfait, Béatrice; Barbarot, Sébastien; Guillot, Bernard; Combemale, Patrick; Ferkal, Salah; Vidaud, Michel; Aubourg, Patrick; Vidaud, Dominique; Wolkenstein, Pierre

    2009-01-01

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder which displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including five quantitative traits (number of café-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas) and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the five quantitative traits ranged from 0.26 to 0.62. Moreover, we investigated for the first time the role of the normal NF1 allele in the variable expression of NF1 through a family-based association study. Nine tag SNPs in NF1 were genotyped in 1132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease. PMID:19417008

  12. Lymphangiopathy in neurofibromatosis 1 manifesting with chylothorax, pericardial effusion, and leg edema

    PubMed Central

    Finsterer, Josef; Stollberger, Claudia; Stubenberger, Elisabeth; Tschakoschian, Sasan

    2013-01-01

    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 the pleural cavity had a long-term beneficial effect on the chylothorax. Leg edema and chylothorax were attributed to affliction of the lymph vessels by the NF-1. Discussion Lymphangiopathy resulting in impaired lymph fluid flow and sequestration of lymph fluid into the pleural sinus and the legs may be a

  13. Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum.

    PubMed

    van der Vaart, T; van Woerden, G M; Elgersma, Y; de Zeeuw, C I; Schonewille, M

    2011-06-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease, characterized by various neurocutaneous symptoms, cognitive impairments and problems in fine and gross motor performance. Although cognitive deficits in NF1 have been attributed to increased release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hippocampus, the origin of the motor deficits is unknown. Cerebellar Purkinje cells, the sole output neurons of the cerebellar cortex, are GABAergic neurons and express neurofibromin at high levels, suggesting an important role for the cerebellum in the observed motor deficits in NF1. To test this, we determined the cerebellar contribution to motor problems in Nf1(+/-) mice, a validated mouse model for NF1. Using the Rotarod, a non-specific motor performance test, we confirmed that, like NF1 patients, Nf1(+/-) mice have motor deficits. Next, to evaluate the role of the cerebellum in these deficits, mice were subjected to cerebellum-specific motor performance and learning tests. Nf1(+/-) mice showed no impairment on the Erasmus ladder, as step time and number of missteps were not different. Furthermore, when compensatory eye movements were tested, no performance deficits were found in the optokinetic reflex and vestibulo-ocular reflex in the dark (VOR) or in the light (VVOR). Finally, Nf1(+/-) mice successfully completed short- and long-term VOR adaptation paradigms, tests that both depend on cerebellar function. Thus, despite the confirmed presence of motor performance problems in Nf1(+/-) mice, we found no indication of a cerebellar component. These results, combined with recent clinical data, suggest that cerebellar function is not overtly affected in NF1 patients.

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

    PubMed

    Shin, Jimann; Padmanabhan, Arun; de Groh, Eric D; Lee, Jeong-Soo; Haidar, Sam; Dahlberg, Suzanne; Guo, Feng; He, Shuning; Wolman, Marc A; Granato, Michael; Lawson, Nathan D; Wolfe, Scot A; Kim, Seok-Hyung; Solnica-Krezel, Lilianna; Kanki, John P; Ligon, Keith L; Epstein, Jonathan A; Look, A Thomas

    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(-/-); p53(e7/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.

  15. Diagnostic value of multiple café-au-lait macules for neurofibromatosis 1 in Chinese children.

    PubMed

    Yao, Ruen; Wang, Lili; Yu, Yongguo; Wang, Jian; Shen, Yiping

    2016-05-01

    Neurofibromatosis 1 (NF1) is a common autosomal dominant condition caused by mutations in the NF1 gene. The appearance of multiple café-au-lait macules is an early sign of the condition, which often alert physicians to follow up and further examine the patient for the possibility of NF1. In order to determine the predictive value of multiple café-au-lait macules at early age for NF1 in Chinese patients, we recruited 19 children who shared the common sign of multiple café-au-lait macules from a general pediatric clinic in Shanghai. All the patients were clinically evaluated following the National Institutes of Health criteria for NF1 and molecular tested for sequence variants and copy number changes. Nine children met the clinical diagnostic criteria of NF1, and molecular tests confirmed all nine patients with pathogenic variants including two genomic deletions, two novel frame-shift variants, four novel nonsense and a splicing variants. In addition, four children who did not meet the diagnostic criteria were also found to carry pathogenic NF1 variants. Overall, 68.4% (13/19) of children with café-au-lait macules and various other clinical presentations were molecularly confirmed with NF1. This study demonstrated that the majority of Chinese children with multiple café-au-lait macules who came to seek for medical attention had NF1. Molecular testing is necessary to be used as an adjunct and sometimes as the main tool for confirming and diagnosing children of NF1 at early age.

  16. Alternative splicing of the neurofibromatosis type I pre-mRNA.

    PubMed

    Barron, Victoria A; Lou, Hua

    2012-04-01

    NF1 (neurofibromatosis type I) is a common genetic disease that affects one in 3500 individuals. The disease is completely penetrant but shows variable phenotypic expression in patients. NF1 is a large gene, and its pre-mRNA undergoes alternative splicing. The NF1 protein, neurofibromin, is involved in diverse signalling cascades. One of the best characterized functions of NF1 is its function as a Ras-GAP (GTPase-activating protein). NF1 exon 23a is an alternative exon that lies within the GAP-related domain of neurofibromin. This exon is predominantly included in most tissues, and it is skipped in CNS (central nervous system) neurons. The isoform in which exon 23a is skipped has 10 times higher Ras-GAP activity than the isoform in which exon 23a is included. Exon 23a inclusion is tightly regulated by at least three different families of RNA-binding proteins: CELF {CUG-BP (cytosine-uridine-guanine-binding protein) and ETR-3 [ELAV (embryonic lethal abnormal vision)-type RNA-binding protein]-like factor}, Hu and TIA-1 (T-cell intracellular antigen 1)/TIAR (T-cell intracellular antigen 1-related protein). The CELF and Hu proteins promote exon 23a skipping, while the TIA-1/TIAR proteins promote its inclusion. The widespread clinical variability that is observed among NF1 patients cannot be explained by NF1 mutations alone and it is believed that modifier genes may have a role in the variability. We suggest that the regulation of alternative splicing may act as a modifier to contribute to the variable expression in NF1 patients.

  17. Sella turcica measurements on lateral cephalograms of patients with neurofibromatosis type 1

    PubMed Central

    Friedrich, Reinhard E.; Baumann, Johanna; Suling, Anna; Scheuer, Hannah T.; Scheuer, Hanna A.

    2017-01-01

    The aim of this study was to measure line segments and areas of sella turcica on lateral cephalograms with respect to the clinical diagnosis of facial phenotype of patients with neurofibromatosis type 1 (NF1). Special attention was given to correlate the measured values with certain tumour types that are typical for this disease. Material and methods: Lateral cephalograms of 194 individuals were investigated. Patients with NF1 were further divided according to the detection and topography of facial plexiform neurofibromas (PNF) taking into account the distribution pattern of the trigeminal nerve. All patients with PNF showed unilateral tumour localisation. Patients without any facial PNF constituted a separate group. Healthy volunteers with ideal occlusion and no history of any intervention in the maxillofacial region served as a control group. The following items were determined on the radiographs: sella entrance, sella width, sella depths, sella diagonal, and sella area. Results: Patients with PNF of the first and second trigeminal nerve branch or affected in all branches showed highly statistically significant enlarged sella tucica measurement values. On the other hand, patients with PNF restricted to one branch only or simultaneously in the second and third branches showed measurement values that were not different to those obtained in NF1 patients devoid of facial PNF. The latter group also showed no difference of sella turcica parameters obtained in the control group. Conclusion: This study provides evidence for the association of a certain NF1 phenotype with distinct skeletal alterations of the skull base, shown here using the example of the representation of the sella turcica in the lateral radiograph. These findings are also relevant in the discussion of NF1 as a disease of bones and in the assessment of brain development in NF1. Both items are discussed in relationship to a facial plexiform neurofibroma. Furthermore, the knowledge of this association of

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

    PubMed

    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.

  19. Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1.

    PubMed

    Ribeiro, Maria J; Violante, Inês R; Bernardino, Inês; Edden, Richard A E; Castelo-Branco, Miguel

    2015-03-01

    Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and

  20. Recurrance of sporadic neurofibromatosis type 1 due to germline mosaicism in the unaffected father

    SciTech Connect

    Lazaro, C.; Gaona, A.; Lynch, M.

    1994-09-01

    Neurofibromatosis type 1 (NF1) or von Recklinghausen disease is one of the most common autosomal dominant disorders in man. In this report we describe a kindred with two affected offspring, in which neither of the parents fulfills the diagnostic criteria of NF1. DNA from peripheral blood was obtained from the family members and from the father`s spermatozoa. Several microsatellite markers, located in intronic regions of the NF1 gene, NF1 cDNA probes, and individual NF1 exons, were analyzed. NF1 microsatellite analysis in the family showed that there was no inheritance of paternal alleles for marker IVS38GT53.0 in the two affected siblings, while they inherited alleles from both parents for other intragenic markers. Hybridization of DNA from the family members with intragenic probes detected abnormal fragments in the lymphocytes from the NF1 individuals and in 10% of father`s spermatozoa, but not in lymphocytes from the parents. The restriction map was consistent with an interstitial deletion of 12 kb. So, we have detected hemizygosity for a microsatellite marker within the NF1 gene, and demonstrated that severe NF1 in a family with recurrence of the diseas, is due to the inheritance of a 12-kb deletion from the clinically unaffected father, who is mosaic for the deletion in his germline cells. This is the first time that germline mosaicism has been demonstrated in NF1. The analysis of the specific NF1 mutation in the sperm of the parent in de novo cases might help in the detection of mosaicism, facilitating genetic counseling.

  1. Functional Connectivity Changes and Executive and Social Problems in Neurofibromatosis Type I.

    PubMed

    Loitfelder, Marisa; Huijbregts, Stephan C J; Veer, Ilya Milos; Swaab, Hanna S; Van Buchem, Mark A; Schmidt, Reinhold; Rombouts, Serge A

    2015-06-01

    Neurofibromatosis type 1 (NF1) has regularly been associated with cognitive, social, and behavioral problems. The fact that many different cognitive and behavioral impairments have been observed in NF1 suggests that networks of brain regions are involved rather than specific brain regions. Here, we examined whether functional connectivity was different in NF1 and, if so, whether associations were present with cognitive, social, and behavioral outcomes. Fourteen NF1 patients (8 male, age: M=12.49, SD=2.65) and 30 healthy controls (HC; 23 male, age: M=12.30, SD=2.94; p=0.835) were included. Functional connectivity was assessed using functional resting-state scanning. We analyzed brain regions that have been associated with cognitive and social functions: the bilateral ventral anterior cingulate cortex (vACC), the bilateral amygdala, the bilateral orbitofrontal cortex (OFC), and the posterior cingulate cortex (PCC). For NF1 patients, connection strengths between brain regions showing HC-NF1 differences were correlated with parent reports of cognitive, social, and behavioral functioning. Compared to HC, patients showed differences in functional connectivity between the left vACC and the frontal cortex, insula, and subcortical areas (caudate, putamen), between the left amygdala and the frontal cortex, insula, supramarginal gyrus, and PCC/precuneus, and between the left OFC and frontal and subcortical areas (caudate, pallidum). In patients, indications were found for associations between increased frontofrontal and temporofrontal functional connectivity with cognitive, social, and behavioral deficits (r-range=0.536-0.851). NF1 patients showed differences in functional connectivity between areas associated with cognitive and social functioning when compared to controls. This, plus the fact that connectivity strengths in these networks were associated with worse cognitive, social, and behavioral outcomes, suggests a neuropathological basis for the widespread deficits

  2. Development of the Adult PedsQL™ Neurofibromatosis Type 1 Module: Initial Feasibility, Reliability and Validity

    PubMed Central

    2013-01-01

    Background Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with significant impact on health-related quality of life (HRQOL). Research in understanding the pathogenetic mechanisms of neurofibroma development has led to the use of new clinical trials for the treatment of NF1. One of the most important outcomes of a trial is improvement in quality of life, however, no condition specific HRQOL instrument for NF1 exists. The objective of this study was to develop an NF1 HRQOL instrument as a module of PedsQL™ and to test for its initial feasibility, internal consistency reliability and validity in adults with NF1. Methods The NF1 specific HRQOL instrument was developed using a standard method of PedsQL™ module development – literature review, focus group/semi-structured interviews, cognitive interviews and experts’ review of initial draft, pilot testing and field testing. Field testing involved 134 adults with NF1. Feasibility was measured by the percentage of missing responses, internal consistency reliability was measured with Cronbach’s alpha and validity was measured by the known-groups method. Results Feasibility, measured by the percentage of missing responses was 4.8% for all subscales on the adult version of the NF1-specific instrument. Internal consistency reliability for the Total Score (alpha =0.97) and subscale reliabilities ranging from 0.72 to 0.96 were acceptable for group comparisons. The PedsQL™ NF1 module distinguished between NF1 adults with excellent to very good, good, and fair to poor health status. Conclusions The results demonstrate the initial feasibility, reliability and validity of the PedsQL™ NF1 module in adult patients. The PedsQL™ NF1 Module can be used to understand the multidimensional nature of NF1 on the HRQOL patients with this disorder. PMID:23432799

  3. First report of factors associated with satisfaction in patients with neurofibromatosis.

    PubMed

    Riklin, Eric; Talaei-Kheoi, Mojtaba; Merker, Vanessa L; Sheridan, Monica R; Jordan, Justin T; Plotkin, Scott R; Vranceanu, Ana-Maria

    2017-03-01

    Patient satisfaction is an integral part of quality health care. We assessed whether health literacy and psychosocial factors are associated with patient satisfaction among adults with neurofibromatosis. Eighty adults (mean age = 44 years; 55% female, 87% white) with NF (50% NF1, 41% NF2, and 9% schwannomatosis) completed an adapted Functional, Communicative, and Critical Health Literacy Questionnaire (FCCHL), the Health Literacy Assessment, a series of Patient Reported Outcome Measures Information System (PROMIS) psychosocial tests, and demographics before the medical visit. After, participants completed two measures of satisfaction: the Medical Interview Satisfaction Scale (MISS) to assess satisfaction with the medical visit, and an adapted version of the Consumer Assessment of Healthcare Providers and Systems Health Literacy Item Set (CAHPS-HL) to assess satisfaction with communication with the provider. Although higher FCCHL health literacy (r = 0.319, P = 0.002), male gender (t = 2.045, P = 0.044) and better psychosocial functioning (r = -0.257 to 0.409, P < 0.05) were associated with higher satisfaction with the medical visit in bivariate correlations, only male gender and higher health literacy remained as significant predictors in multivariable analyses. Higher FCCHL health literacy, less pain interference, fewer pain behaviors, and higher satisfaction with social roles and social discretionary activities (r = -0.231 to 0.331, P < 0.05) were associated with higher satisfaction with the communication with the provider in bivariate analyses. Results support the use of psychosocial and health literacy measures in clinical practice. Referrals to psychosocial treatments in addition to brief interventions focused on increasing health literacy may also be beneficial. © 2017 Wiley Periodicals, Inc.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  8. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden.

    PubMed

    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.

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

    PubMed Central

    Shin, Jimann; Padmanabhan, Arun; de Groh, Eric D.; Lee, Jeong-Soo; Haidar, Sam; Dahlberg, Suzanne; Guo, Feng; He, Shuning; Wolman, Marc A.; Granato, Michael; Lawson, Nathan D.; Wolfe, Scot A.; Kim, Seok-Hyung; Solnica-Krezel, Lilianna; Kanki, John P.; Ligon, Keith L.; Epstein, Jonathan A.; Look, A. Thomas

    2012-01-01

    SUMMARY 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. PMID:22773753

  10. Bone mineral density in children and young adults with neurofibromatosis type 1.

    PubMed

    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.

  11. Ependimoma myxopapilar sacro gigante con osteolisis

    PubMed Central

    Ajler, Pablo; Landriel, Federico; Goldschmidt, Ezequiel; Campero, Álvaro; Yampolsky, Claudio

    2014-01-01

    Objetivo: la presentación de un caso de una paciente con un ependimoma sacro con extensa infiltración y destrucción ósea local. Descripción del caso: una mujer de 53 años acudió a la consulta por dolor lumbosacro y alteraciones sensitivas perineales y esfinterianas. La imágenes por Resonancia Magnética (IRM) y la Tomografía Axial Computada (TAC) mostraron una lesión expansiva gigante a nivel S2-S4 con extensa osteólisis e invasión de tejidos adyacentes. Se realizó una exéresis tumoral completa con mejoría del estatus funcional. La anatomía patológica informó ependimoma mixopapilar. Discusión: la extensión de la resección quirúrgica es el mejor predictor de buen pronóstico. El tratamiento radiante se reserva como opción adyuvante para las resecciones incompletas y recidiva tumoral. La quimioterapia sólo debería utilizarse en casos en que la cirugía y la radioterapia estén contraindicadas. Conclusión: Los ependimomas mixopapilares sacros con destrucción ósea y presentación intra y extradural son muy infrecuentes y deben ser tenidos en cuenta entre los diagnósticos diferenciales preoperatorios. Su resección total, siempre que sea posible, es la mejor alternativa terapéutica. PMID:25165615

  12. Biome depletion in conjunction with evolutionary mismatches could play a role in the etiology of neurofibromatosis 1.

    PubMed

    Beales, Donna L

    2015-04-01

    Neurofibromatosis 1 (NF1) arises de novo in a striking 30-50% of cases, pointing toward an environmental etiology, though none has been clearly identified. The Biome Depletion Theory posits that the absence of mutualistic and commensal organisms within the human body coupled with modern lifestyle alterations may have profoundly deleterious effects, inclusive of immunologic derangement that is thought to result in allergy, atopy, and numerous autoimmune diseases. Biome depletion has been implicated as a factor in the etiology of both multiple sclerosis and autism spectrum disorders; biome reconstitution, i.e. replenishment of the biome with certain keynote species, is being used in the treatment of these and other autoimmune states. Neurofibromatosis 1 has been associated with allergy, various autoimmune states, multiple sclerosis, and autism. Recent research has posited that NF1, multiple sclerosis and autism may all arise from disturbances in the neural crest during gestation. This paper hypothesizes that there is indirect evidence that a highly inflammatory uterine state may precipitate epigenetic changes in vulnerable NF-related genes in the course of fetal development. The etiology of NF1 may lie in the absence of immunomodulation by commensal and mutualistic species once ubiquitously present in the environment, as well as through adoption of a modern lifestyle that contributes to chronic inflammation. Replenishment of helminths and other missing organisms to the human biome prior to conception as well as addressing nutritional status, psychological stress, and environmental exposures may prevent the development of NF1.

  13. Surgical care burden in orbito-temporal neurofibromatosis: Multiple procedures and surgical care duration analysis in 47 consecutive adult patients.

    PubMed

    Pessis, Rachel; Lantieri, Laurent; Britto, Jonathan A; Leguerinel, Caroline; Wolkenstein, Pierre; Hivelin, Mikaël

    2015-10-01

    Patients with orbito-temporal neurofibromatosis (OTNF) bear a heavy burden of surgical care. We studied 47 consecutive patients with OTNF from the French Neurofibromatosis 1 Referral Center cohort (n > 900), over a 15-year period to determine the clinical features most likely to predict repeat surgery and longer duration of surgical care. Forty-seven patients (5.2% of the NF1 patients' cohort) underwent 79 procedures with a 4.8 years average follow-up. Soft-tissue surgery had a high revision rate (19/45 patients), skeletal surgery did not (2/13 patients). Transosseous wire canthopexy and facial aesthetic unit remodeling were associated with stable outcome. Ptosis repair carried an unfavorable outcome, particularly in the presence of sphenoid dysplasia. Stable skeletal remodeling was achieved with polyethylene implants and/or cementoplasty. Multiple procedures were undertaken in 70% of patients and were predicted by the NF volume, canthopexy, skeletal dysplasia, or a Jackson's classification 2 and/or 3; but not by declining visual acuity. A classification based upon predictive risk of repeated procedures is proposed: Group 1: Isolated soft tissue infiltration not requiring levator palpebrae or canthal surgery; Group 2: Soft tissue involvement requiring ptosis repair or canthopexy, or NF great axis over 4.5 cm; Group 3: Presence of sphenoid dysplasia with pulsatile proptosis, regardless of visual acuity.

  14. Neurofibromatosis Type 1 and the “Elephant Man's” Disease: The Confusion Persists: An Ethnographic Study

    PubMed Central

    Legendre, Claire-Marie; Charpentier-Côté, Catherine; Drouin, Régen; Bouffard, Chantal

    2011-01-01

    Background During informal interviews in the course of an ethnographic study on intergenerational dialogue between individuals with neurofibromatosis and their parents, many members of Canadian neurofibromatosis associations stated they continue to be told the condition that afflicts them or their children is the “elephant man's” disease. Today, even though well established clinical criteria make it possible to diagnose and differentiate the two diseases, the confusion between NF1 and the disease of Joseph Merrick, the “elephant man”, persists in both media representations and those of physicians. The objective of this article is to document the persistence of this confusion, to identify the factors that contribute to it, and to identify its impact on the well being of individuals with NF1. Methodology Preliminary stages of an ethnographic study. Principal Findings Our findings show that some reference sources, past medical training, and print and online news media have all contributed to the persistence of the association between NF1 and the disease of Joseph Merrick, the “elephant man”. Our observations suggest that this misconception can have negative medical, social, and psychological impacts on patients and their families and thus increase the burden of the disease. Conclusions Changes of attitude regarding medical teaching and the media could lead to definitively clearing up the confusion. PMID:21347399

  15. The Role of [18F]FDG-PET/CT in Predicting Malignant Transformation of Plexiform Neurofibromas in Neurofibromatosis-1

    PubMed Central

    Abdul Razak, Muzib; London, Kevin

    2016-01-01

    Background. Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to diagnose and treat and contribute to significant morbidity and mortality for patients with Neurofibromatosis-1 (NF-1). FDG-PET/CT is being increasingly used as an imaging modality to discriminate between benign and malignant plexiform neurofibromas. Objectives. To assess the value of FDG-PET/CT in differentiating between benign and malignant peripheral nerve lesions for patients with Neurofibromatosis-1. Methods. A systematic review of the literature was performed prior to application of stringent selection criteria. Ultimately 13 articles with 796 tumours were deemed eligible for inclusion into the review. Results. There was a significant difference between mean SUVmax of benign and malignant lesions (1.93 versus 7.48, resp.). Sensitivity ranged from 89 to 100% and specificity from 72 to 94%. ROC analysis was performed to maximise sensitivity and specificity of SUVmax cut-off; however no clear value was identified (range 3.1–6.1). Significant overlap was found between the SUVmax of benign and malignant lesions making differentiation of lesions difficult. Many of the studies suffered from having a small cohort and from not providing histological data on all lesions which underwent FDG-PET/CT. Conclusion. This systematic review is able to demonstrate that FDG-PET/CT is a useful noninvasive test for discriminating between benign and malignant lesions but has limitations and requires further prospective trials. PMID:28058117

  16. Somatic deletion of the NF1 gene in a neurofibromatosis type 1-associated malignant melanoma demonstrated by digital PCR

    PubMed Central

    Rübben, Albert; Bausch, Birke; Nikkels, Arjen

    2006-01-01

    Background Neurofibromatosis type 1 (NF1) is the most common hereditary neurocutaneous disorder and it is associated with an elevated risk for malignant tumors of tissues derived from neural crest cells. The NF1 gene is considered a tumor suppressor gene and inactivation of both copies can be found in NF1-associated benign and malignant tumors. Melanocytes also derive from neural crest cells but melanoma incidence is not markedly elevated in NF1. In this study we could analyze a typical superficial spreading melanoma of a 15-year-old boy with NF1 for loss of heterozygosity (LOH) within the NF1 gene. Neurofibromatosis in this patient was transmitted by the boy's farther who carried the mutation NF1 c. 5546 G/A. Results Melanoma cells were isolated from formalin-fixed tissue by liquid coverslip laser microdissection. In order to obtain statistically significant LOH data, digital PCR was performed at the intragenic microsatellite IVS27AC28 with DNA of approx. 3500 melanoma cells. Digital PCR detected 23 paternal alleles and one maternal allele. Statistical analysis by SPRT confirmed significance of the maternal allele loss. Conclusion To our knowledge, this is the first molecular evidence of inactivation of both copies of the NF1 gene in a typical superficial spreading melanoma of a patient with NF1. The classical double-hit inactivation of the NF1 gene suggests that the NF1 genetic background promoted melanoma genesis in this patient. PMID:16961930

  17. RELACIÓN MÉDICO PACIENTE: DERECHOS DEL ADULTO MAYOR

    PubMed Central

    Barrantes-Monge, Melba; Rodríguez, Eduardo; Lama, Alexis

    2009-01-01

    Existen prejuicios en relación con la vejez, incluso entre los profesionales que se dedican a la gerontología. Uno común y peligroso es considerar que los viejos son todos enfermos o discapacitados. La relación médico-paciente es la piedra angular de la práctica y ética médicas. Para alcanzar el respeto por los adultos mayores es necesaria una medicina prudente, basada en una práctica en la cual la reflexión ética y clínica pueda contribuir. Esto último es posible si se hacen valer los derechos del adulto mayor, en particular como paciente para la toma de decisiones. PMID:20379380

  18. Secondary Knee Osteoarthritis due to Neurofibromatosis Type 1 Treated with above the Knee Amputation: A Case Report.

    PubMed

    Patel, Jay; Whiting, Jeffrey; Jones, Daniel

    2013-01-01

    Background. Neurofibromatosis Type 1 (NF-1) has a variety of associated orthopaedic manifestations that have been previously reported. We report a case of severe, grade 4 knee osteoarthritis (OA) with recurrent subluxation and joint laxity due to multiple extra-articular neurofibromas ultimately treated with Above the Knee Amputation (AKA). Case Description. A 39-year-old man presented with multiple neurofibromas and lymphedema leading to degenerative changes of the knee. Conservative treatment failed due to the severity of the knee degeneration and patient discomfort. Likewise, arthroplasty was not possible due to poor bone quality and joint instability. Therefore, AKA was selected to relieve symptoms and provide functional improvement. six months after the procedure the patient has increased functional capacity for ambulation and activities of daily living, as well as significant decrease in pain and discomfort. Clinical Relevance. Extra-articular neurofibromas causing severe secondary OA in relatively young patients can be functionally improved with AKA and prosthetic device use.

  19. Preservation of auditory and vestibular function after surgical removal of bilateral vestibular schwannomas in a patient with neurofibromatosis type 2

    NASA Technical Reports Server (NTRS)

    Black, F. O.; Brackmann, D. E.; Hitselberger, W. E.; Purdy, J.

    1995-01-01

    The outcome of acoustic neuroma (vestibular schwannoma) surgery continues to improve rapidly. Advances can be attributed to several fields, but the most important contributions have arisen from the identification of the genes responsible for the dominant inheritance of neurofibromatosis types 1 (NF1) and 2 (NF2) and the development of magnetic resonance imaging with gadolinium enhancement for the early anatomic confirmation of the pathognomonic, bilateral vestibular schwannomas in NF2. These advances enable early diagnosis and treatment when the tumors are small in virtually all subjects at risk for NF2. The authors suggest that advising young NF2 patients to wait until complications develop, especially hearing loss, before diagnosing and operating for bilateral eighth nerve schwannomas may not always be in the best interest of the patient. To the authors' knowledge, this is the first reported case of preservation of both auditory and vestibular function in a patient after bilateral vestibular schwannoma excision.

  20. Multifocal Head and Neck Neurofibromas with Osseous Abnormalities and Muscular Hypoplasia in a Child with Neurofibromatosis: Type I.

    PubMed

    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.

  1. Solitary Encapsulated Neurofibroma Not Associated with Neurofibromatosis-1 Affecting Tongue in a 73-Year-Old Female

    PubMed Central

    Mahmud, Sk. Abdul; Chattaraj, Moumita; Gayen, Swagata

    2016-01-01

    Neurofibromas are benign tumors of nerve cell origin arising due to proliferation of Schwann cells and fibroblasts. They are usually asymptomatic and hence remain undiagnosed. They are commonly found on the skin and intraorally tongue is the most common site for their occurrence. Here, we present a unique case of solitary encapsulated neurofibroma in the oral cavity without any clinical manifestations or family history of Neurofibromatosis type 1 in a 73-year-old female patient who presented with a painless swelling on the tongue. The histopathologic findings closely mimicked benign fibrous histiocytoma. In our case, definitive diagnosis of neurofibroma was made based on clinical findings, family history, and histopathological and immunohistochemical evaluation. Through this case report we want to emphasize the role of biopsy and immunohistochemistry in arriving at a confirmatory diagnosis. The patient was treated by surgical excision and showed no signs of recurrence over a follow-up period of 12 months. PMID:27525129

  2. Multifocal Head and Neck Neurofibromas with Osseous Abnormalities and Muscular Hypoplasia in a Child with Neurofibromatosis: Type I

    PubMed Central

    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. PMID:27382495

  3. A Novel Medical Treatment of Cushing's Due to Ectopic ACTH in a Patient With Neurofibromatosis Type 1

    PubMed Central

    Bano, Gul; Mir, Farheen; Beharry, Nigel; Wilson, Philip; Hodgson, Shirley; Schey, Stephen

    2012-01-01

    A 64-year-old male presented with neurofibromatosis 1 and Cushing’s syndrome. Clinically he was over weight, depressed with extensive skin bruising and hypertension. His 24 hours urinary metanephrines, urinary 5HIAA, gut peptides and chromgranin levels were normal. His renal function and renal MRI scan was also normal. His cortisol failed to suppress on overnight dexamethsone suppression test. His low dose dexamethasone suppression with CRH stimulation showed failure of suppression of cortisol to < 50 nmol/L and ACTH was measurable at 10 ng/L on day 3. There was no response of ACTH or cortisol to CRH stimulation. His ACTH precursors were high at 126 pmol/L consistent with defective pro-opiomelanocortin (POMC) processing suggesting an ectopic source of ACTH production. The MRI scan of his pituitary and CT scan of the adrenal glands was normal. His octreotide scan was negative. The source of his ectopic ACTH was most likely a large retroperitoneal plexiform neurofibroma seen on CT abdomen that had undergone malignant peripheral nerve sheath tumour transformation on histology. He was a poor surgical risk for tumour debulking procedure. In view of the available literature and role of c-kit signalling in neurofibromatosis, he was treated with Imitinib. Four months after the treatment his Cushings had resolved on biochemical testing. After a year his plexiform neurofibroma has not increased in size. To our knowledge, this is the first case of NF1 associated with clinical and biochemical features of Cushing’s secondary to ectopic ACTH due to MPNST in a plexiform neurofibroma and its resolution on treatment with imatinib. PMID:23853621

  4. A Novel Medical Treatment of Cushing's Due to Ectopic ACTH in a Patient With Neurofibromatosis Type 1.

    PubMed

    Bano, Gul; Mir, Farheen; Beharry, Nigel; Wilson, Philip; Hodgson, Shirley; Schey, Stephen

    2013-01-01

    A 64-year-old male presented with neurofibromatosis 1 and Cushing's syndrome. Clinically he was over weight, depressed with extensive skin bruising and hypertension. His 24 hours urinary metanephrines, urinary 5HIAA, gut peptides and chromgranin levels were normal. His renal function and renal MRI scan was also normal. His cortisol failed to suppress on overnight dexamethsone suppression test. His low dose dexamethasone suppression with CRH stimulation showed failure of suppression of cortisol to < 50 nmol/L and ACTH was measurable at 10 ng/L on day 3. There was no response of ACTH or cortisol to CRH stimulation. His ACTH precursors were high at 126 pmol/L consistent with defective pro-opiomelanocortin (POMC) processing suggesting an ectopic source of ACTH production. The MRI scan of his pituitary and CT scan of the adrenal glands was normal. His octreotide scan was negative. The source of his ectopic ACTH was most likely a large retroperitoneal plexiform neurofibroma seen on CT abdomen that had undergone malignant peripheral nerve sheath tumour transformation on histology. He was a poor surgical risk for tumour debulking procedure. In view of the available literature and role of c-kit signalling in neurofibromatosis, he was treated with Imitinib. Four months after the treatment his Cushings had resolved on biochemical testing. After a year his plexiform neurofibroma has not increased in size. To our knowledge, this is the first case of NF1 associated with clinical and biochemical features of Cushing's secondary to ectopic ACTH due to MPNST in a plexiform neurofibroma and its resolution on treatment with imatinib.

  5. Relationship between whole-body tumor burden, clinical phenotype, and quality of life in patients with neurofibromatosis.

    PubMed

    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.

  6. ConSCRIPT

    PubMed Central

    Mottarella, Scott E.; Rosa, Mario; Bangura, Abdul; Bernstein, Herbert J.; Craig, Paul A.

    2011-01-01

    The aim of the Structural Biology Extensible Visualization Scripting Language (SBEVSL) project is to allow users who are experts in one scripting language to use that language in a second molecular visualization environment without requiring the user to learn a new scripting language. ConSCRIPT, the first SBEVSL release, is a plug-in for PyMOL that accepts RasMol scripting commands either as premade scripts or as line-by-line entries from PyMOL's own command line. The plug-in is available for download at http://sourceforge.net/projects/sbevsl/files in the ConSCRIPT folder. PMID:21567873

  7. Hemidiaphragmatic palsy following excision of cervical dumbbell neurofibroma in a patient with neurofibromatosis: Importance of assessing functional status of "non-limb" roots.

    PubMed

    Krishnan, Prasad; Kartikueyan, Rajaraman; Kumar, Soumen K

    2016-01-01

    A 27-year-old male patient with neurofibromatosis type 1 who was operated on for a dumbbell neurofibroma of the cervical spine developed transient respiratory difficulty due to postoperative unilateral diaphragmatic palsy. This report emphasizes the need for preoperative assessment of residual function in involved non-limb roots, the role of intraoperative monitoring to take a decision on root sacrifice, and the need for optimizing respiratory function preoperatively, and describes a complication rarely reported in literature.

  8. Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis

    DTIC Science & Technology

    2014-06-01

    Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Patients with Neurofibromatosis ( NF1 ) exhibit deficient...bone healing/ The cause of poor bone healing in NF1 is unclear, and pharmacologic approaches to improve bone repair are lacking. Beta-catenin is a...undifferentiated fibroblast-like cells persist at the fracture site, resulting in a pseudarthrosis. Genetically engineered mice in which the Nf1 gene can be

  9. The Con Test

    ERIC Educational Resources Information Center

    Fletcher, Michael

    2009-01-01

    In this article, the author describes the format of the Con Test, an Australian television game show which followed the same general rules and game play as the UK show PokerFace. At the end of each round a contestant needs to decide whether or not he or she should fold. A contestant needs to know how likely it is that he or she is in last place.…

  10. Rare case of optic pathway glioma with extensive intra-ocular involvement in a child with neurofibromatosis type 1.

    PubMed

    Gupta, Vasudha; Sabri, Kourosh; Whelan, Kaitlyn F; Viscardi, Virginia

    2015-01-01

    We present a case of a 3-year-old girl with a positive family history of neurofibromatosis type-1 (NF1) presented with best corrected visual acuity of 20/40 in the right eye and <20/400 in the left eye. External ocular examination revealed left eye proptosis of 3 mm, grade II left relative afferent pupillary defect and full range of ocular motility with no strabismus. Slit lamp examination revealed iris lisch nodules bilaterally. Dilated fundus examination of the right eye was normal. Left eye disclosed a large mass extending from the optic nerve head, with associated subretinal fluid. There was neovascularization at the optic disc as well as a superior retinal hemorrhage. Computed tomography of brain/orbits showed an enlarged left optic nerve with a large mass at the optic nerve head, with no evidence of calcification. In addition, a large left optic pathway glioma (OPG), multiple hamartomas within the brain and a smaller low-grade right OPG was also reported. The remarkable feature of our case is the rare intraocular optic nerve involvement of the OPG. Early and regular ophthalmological assessment of all NF1 suspect/confirmed cases is of paramount importance in order to detect OPG early, resulting in timely intervention and salvage of vision.

  11. 3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.

    PubMed

    Anderson, David M G; Van de Plas, Raf; Rose, Kristie L; Hill, Salisha; Schey, Kevin L; Solga, Anne C; Gutmann, David H; Caprioli, Richard M

    2016-10-21

    Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions.

  12. The cyclic AMP pathway is a sex-specific modifier of glioma risk in type 1 neurofibromatosis patients

    PubMed Central

    Warrington, Nicole M.; Sun, Tao; Luo, Jingqin; McKinstry, Robert C.; Parkin, Patricia C.; Ganzhorn, Sara; Spoljaric, Debra; Albers, Anne C.; Merkelson, Amanda; Stewart, Douglas R.; Stevenson, David A.; Viskochil, David; Druley, Todd E.; Forys, Jason T; Reilly, Karlyne M.; Fisher, Michael J.; Tabori, Uri; Allen, Jeffrey C.; Schiffman, Joshua D.; Gutmann, David H.; Rubin, Joshua B.

    2014-01-01

    Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1. PMID:25381154

  13. Magnetic Resonance Imaging in a Neurofibromatosis Type 2 Patient with a Novel MRI-Compatible Auditory Brainstem Implant

    PubMed Central

    Shew, Matthew; Bertsch, Judson; Camarata, Paul; Staecker, Hinrich

    2017-01-01

    Auditory brainstem implantation has become a key technique for the rehabilitation of hearing in patients with neurofibromatosis type 2. The nature of this devastating genetic disease requires ongoing MRI for the patient's lifespan. Today, most auditory brainstem implants require removal of the magnet that connects the internal device to the external speech processor to undergo imaging as their disease progresses. Patients have the option of having a short procedure to have the magnet taken out and replaced each time, or alternately using a headband to secure the processor over the receiver coil of the internal device. Novel magnet technology has led to the development of a freely rotating magnet that can be used inside the magnetic field of an MRI scanner without losing magnet strength and without being displaced from the body of the device. We report one of the first patients implanted with a Med-El Synchrony ABI in the United States who subsequently underwent successful imaging with MRI 1.5 tesla to follow for other existing schwannomas. PMID:28210535

  14. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    NASA Astrophysics Data System (ADS)

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-11-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

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

    PubMed

    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.

  16. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes.

    PubMed Central

    Easton, D F; Ponder, M A; Huson, S M; Ponder, B A

    1993-01-01

    Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component, we examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored--number of café-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored--the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For café-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression, but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other "modifying" loci and that these modifying genes are trait specific. PMID:8328449

  17. Attitudes about internet support groups among adolescents and young adults with neurofibromatosis type 1 and their parents.

    PubMed

    Martin, Staci; Wolters, Pamela L; Baldwin, Andrea; Roderick, Marie Claire; Toledo-Tamula, Mary Anne; Gillespie, Andrea; Widemann, Brigitte

    2014-10-01

    Youth with neurofibromatosis type 1 (NF1) have multiple, complex symptoms associated with physical, social-emotional, and cognitive difficulties. In addition, caring for a child with NF1 can be extremely challenging for parents. Since research with other chronic illness populations suggests that social support, including internet support groups (ISGs), can be beneficial, this survey study aimed to determine the attitudes and preferences of adolescents and young adults with NF1 and parents of a child with NF1 regarding ISGs. Thirty patients and 30 caregivers completed a 24-item survey about ISGs. Many patients and parents are not aware of any ISGs for NF1, but are interested in using one in the future for a variety of reasons, including to get answers to their questions about NF1, to find out about research studies, and to discuss problems and concerns about NF1. Specific concerns of interest include physical, social-emotional, and cognitive aspects of NF1. ISGs have potential as a social support intervention within the NF1 community. ISGs for the NF1 population should include patients with NF1 (or parents of children with NF1) as well as a health professional, and both chat rooms and discussion boards likely would be well-received.

  18. Café-au-lait macules and intertriginous freckling in piebaldism: clinical overlap with neurofibromatosis type 1 and Legius syndrome.

    PubMed

    Stevens, Cathy A; Chiang, Pei-Wen; Messiaen, Ludwine M

    2012-05-01

    Piebaldism is an autosomal dominant disorder characterized by congenital hypopigmented patches of skin and hair and has been found to be associated with mutations in the KIT or SLUG genes. Café-au-lait macules (CALM) may occasionally be seen in piebaldism. There are four reports describing six patients who were said to have both piebaldism and neurofibromatosis type 1 (NF1) due to the presence of multiple CALM and intertriginous freckling, but none of these patients had undergone comprehensive NF1 mutation analysis. We describe a large family with piebaldism in which two members meet diagnostic criteria for NF1 based on the presence of >5 CALM and intertriginous freckling. Interestingly, only these two family members are of mixed race, which could be of importance. A novel complex mutation in the KIT gene was identified in several family members affected with piebaldism; the proband meeting diagnostic criteria for NF1 also underwent comprehensive NF1 and SPRED1 testing with no mutations detected. These findings suggest that piebaldism may occasionally include CALM and intertriginous freckling, which may create diagnostic confusion especially in the absence of a family history of piebaldism. However, careful clinical evaluation and molecular testing if necessary should distinguish these two disorders.

  19. Coexistence of Juvenile-Like Polyp with Neurofibroma at the Gastroesophageal Junction in an Adult with Neurofibromatosis Type I

    PubMed Central

    Iqbal, Atif

    2017-01-01

    A 23-year-old Caucasian male with Neurofibromatosis Type I (NF-I) was found to have a submucosal nodule at the gastroesophageal junction (GEJ) and underwent endoscopic submucosal dissection. Histological examination revealed two different lesions within the nodule. The dominant lesion was inflammatory/hyperplastic (juvenile-like) polyp with obliterative vasculopathy while the smaller lesion was a neurofibroma. Gastric/GEJ lesions in NF-I are very rare with only seven cases reported in the literature. Three cases of juvenile-like gastric polyps (located in the antrum, greater curvature, and fundus) have been reported in adult NF-I patients. An inflammatory polyp associated with a neurofibroma has only been described once in the pediatric literature but never in an adult. Our case is unique from those previously described in the literature due to the age of the patient, the presence of 2 histologically separate lesions in one endoscopically evident lesion, and the presence of obliterative vasculopathy in the juvenile-like polyp. PMID:28168076

  20. Café-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind?

    PubMed

    De Schepper, Sofie; Boucneau, Joachim; Vander Haeghen, Yves; Messiaen, Ludwine; Naeyaert, Jean-Marie; Lambert, Jo

    2006-04-01

    Solitary café-au-lait spots are quite common in the general population but multiple café-au-lait macules (CALM) are often indicative of an underlying genetic disorder. The frequency of having more than five CALM is rare in normal individuals and is therefore considered as a cut-off for the diagnosis of neurofibromatosis type 1 (NF1). The etiopathogenesis of these macules is still very obscure. In this study we compared epidermal melanocyte and dermal mast cell numbers between four groups: control normal and control CALM skin, and NF1 normal and NF1 CALM skin and elaborated a possible role for stem cell factor (SCF) in CALM formation. The groups were analyzed by immunohistochemistry for numerical analysis of the melanocyte and mast cell population and by ELISA, western blot analysis and real-time quantitative PCR for further determination of the role of SCF. We found a significant increase in melanocyte density in NF1 CALM skin compared with the isolated CALM in control individuals. However, both groups displayed a similar increase in mast cell density. In addition, we found increased levels of soluble SCF in NF1 CALM and in NF1 normal fibroblast supernatant. We conclude that SCF is an important cytokine in NF1 skin, but that additional (growth) factors and/or genetic mechanisms are needed to induce NF1-specific CALM hyperpigmentation.

  1. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    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.

  2. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis.

    PubMed

    Fisher, Michael J; Loguidice, Michael; Gutmann, David H; Listernick, Robert; Ferner, Rosalie E; Ullrich, Nicole J; Packer, Roger J; Tabori, Uri; Hoffman, Robert O; Ardern-Holmes, Simone L; Hummel, Trent R; Hargrave, Darren R; Bouffet, Eric; Charrow, Joel; Bilaniuk, Larissa T; Balcer, Laura J; Liu, Grant T

    2012-06-01

    Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.

  3. In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

    PubMed Central

    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

    2015-01-01

    “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. PMID:26150484

  4. Cerebral glucose metabolism in neurofibromatosis type 1 assessed with [18F]-2-fluoro-2-deoxy-D-glucose and PET.

    PubMed Central

    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 finding suggests that the abnormalities seen on MRI are not due to defective blood supply, localised oedema, or grey matter heterotopic foci as previously hypothesised. The presence of the hypometabolic areas seems to be inconsistently related to the occurrence of seizures and is not proportional to the degree of mental impairment. This study provides evidence of a widespread cerebral hypometabolism that is not related to the presence of MRI abnormalities; conversely normal metabolism was present in the areas with an abnormal MRI signal. Images PMID:7798976

  5. Magnetic Resonance Imaging in a Neurofibromatosis Type 2 Patient with a Novel MRI-Compatible Auditory Brainstem Implant.

    PubMed

    Shew, Matthew; Bertsch, Judson; Camarata, Paul; Staecker, Hinrich

    2017-01-01

    Auditory brainstem implantation has become a key technique for the rehabilitation of hearing in patients with neurofibromatosis type 2. The nature of this devastating genetic disease requires ongoing MRI for the patient's lifespan. Today, most auditory brainstem implants require removal of the magnet that connects the internal device to the external speech processor to undergo imaging as their disease progresses. Patients have the option of having a short procedure to have the magnet taken out and replaced each time, or alternately using a headband to secure the processor over the receiver coil of the internal device. Novel magnet technology has led to the development of a freely rotating magnet that can be used inside the magnetic field of an MRI scanner without losing magnet strength and without being displaced from the body of the device. We report one of the first patients implanted with a Med-El Synchrony ABI in the United States who subsequently underwent successful imaging with MRI 1.5 tesla to follow for other existing schwannomas.

  6. Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform.

    PubMed

    Calì, Francesco; Chiavetta, Valeria; Ruggeri, Giuseppa; Piccione, Maria; Selicorni, Angelo; Palazzo, Daniela; Bonsignore, Maria; Cereda, Anna; Elia, Maurizio; Failla, Pinella; Figura, Maria Grazia; Fiumara, Agata; Maitz, Silvia; Luana Mandarà, Giuseppa Maria; Mattina, Teresa; Ragalmuto, Alda; Romano, Corrado; Ruggieri, Martino; Salluzzo, Roberto; Saporoso, Antonino; Schepis, Carmelo; Sorge, Giovanni; Spanò, Maria; Tortorella, Gaetano; Romano, Valentino

    2017-02-01

    Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.

  7. In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells.

    PubMed

    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.

  8. Relations between fine motor skill and parental report of attention in young children with neurofibromatosis type 1.

    PubMed

    Casnar, Christy L; Janke, Kelly M; van der Fluit, Faye; Brei, Natalie G; Klein-Tasman, Bonita P

    2014-01-01

    Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders presenting in approximately 1 in 3,500 live births. NF1 is a highly variable condition with a large number of complications. A common complication is neuropsychological problems, including developmental delays and learning difficulties that affect as many as 60% of patients. Research has suggested that school-aged children with NF1 often have poorer fine motor skills and are at greater risk for attention difficulties than the general population. Thirty-eight children with NF1 and 23 unaffected children between the ages of 4 and 6 years, who are enrolled in a study of early development in NF1, were included in the present study. Varying levels of fine motor functioning were examined (simple to complex fine motor tasks). For children with NF1, significant difficulties were demonstrated on lab-based mid-level and complex fine motor tasks, even after controlling for nonverbal reasoning abilities, but not on simple fine motor tasks. Parental report also indicated difficulties in everyday adaptive fine motor functioning. No significant correlations were found between complex fine motor ability and attention difficulties. This study provides much needed descriptive data on the early emergence of fine motor difficulties and attention difficulties in young children with NF1.

  9. Severe Hypercholesterolemia: A Unique Presentation of Non-Hodgkin's Lymphoma in a Patient with Neurofibromatosis Type 1

    PubMed Central

    Anyadike, Nnaemeka; Rahmani, Rabin

    2014-01-01

    We report a case of non-Hodgkin's lymphoma (NHL) with an unusual initial manifestation as severe hypercholesterolemia and obstructive jaundice in a patient with neurofibromatosis type 1 (NF 1). NHL should be considered in the evaluation of obstructive jaundice alone or in combination with severe hypercholesterolemia. Relief of biliary obstruction led to the resolution of hypercholesterolemia in our 59-year-old male patient, followed by doxorubicin-based chemotherapy for the underlying lymphoma. NF 1 is a genetic condition that results from a defect in a tumor-suppressor gene and it is likely that this led to the development of NHL in our patient. It is important that clinicians are familiar with the gastrointestinal manifestations of NF 1, especially its association with intra-abdominal malignancies, when treating patients with a personal or family history. To the best of our knowledge, this is the first case of NHL presenting initially as severe hypercholesterolemia and it is also one of the few instances where NHL has been reported in association with NF 1. PMID:25093126

  10. Case Report: A Rosette-forming Glioneuronal Tumor in the Tectal Plate in a Patient with Neurofibromatosis Type I

    PubMed Central

    Payne, Russell; Langan, Sara; Specht, Charles S

    2016-01-01

    We report the case of a 41–year-old female with neurofibromatosis Type 1 (NF1) who developed a rosette-forming glioneuronal tumor (RGNT) in the tectal plate. This tumor was diagnosed in 2002 when the patient presented with obstructive hydrocephalus, which was subsequently treated with a ventriculoperitoneal shunt and then an endoscopic third ventriculostomy. Initially thought to be a pilocytic astrocytoma, it was followed with serial magnetic resonance imaging (MRI) until tumor progression and development of a large fourth ventricular cystic component prompted resection via suboccipital craniotomy. Histological examination demonstrated an RGNT, a WHO Grade 1 tumor, with neurocytic rosettes, perivascular pseudorosettes, and elements resembling a pilocytic astrocytoma. Initially, the patient did well after her craniotomy, but postoperative complications set in that eventually led to her death. In this case report, we describe a relatively rare tumor that, despite its benign nature, leads to frequent complications and deficits due to its surgically challenging location. Along with previously reported examples, this cases raises the possibility of a causal relationship between NF1 and RGNT.  PMID:27917325

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  15. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    PubMed Central

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs. PMID:27833160

  16. Neurofibromatosis type 1 (NF1): a protein truncation assay yielding identification of mutations in 73% of patients.

    PubMed Central

    Park, V M; Pivnick, E K

    1998-01-01

    Neurofibromatosis type 1 (NF1) is caused by mutations in a tumour suppressor gene located on chromosome 17 (17q11.2). Disease causing mutations are dispersed throughout the gene, which spans 350 kilobases and includes 59 exons. A common consequence of NF1 mutations is introduction of a premature stop codon, and the majority of mutant genes encode truncated forms of neurofibromin. We used a protein truncation assay to screen for mutations in 15 NF1 patients and obtained positive results in 11 of them (73%). Sequencing of cDNA and genomic DNA yielded identification of 10 different mutations, including four splicing errors, three small deletions, two nonsense mutations, and one small insertion. Nine mutations were predicted to cause premature termination of translation, while one mutation caused in frame deletion as a result ofexon skipping. In one other case involving abnormal splicing, five different aberrantly spliced transcripts were detected. One germline nonsense mutation (R1306X, 3916C>T) corresponded to the same base change that occurs by mRNA editing in normal subjects. The second nonsense mutation (R2496X) was the sole germline mutation that has been previously described. The subjects studied represented typically affected NF1 patients and no correlations between genotype and phenotype were apparent. A high incidence of ocular hypertelorism was observed. Images PMID:9783703

  17. Toward a Survey of Somatic Mutation of the NF1 Gene in Benign Neurofibromas of Patients with Neurofibromatosis Type 1

    PubMed Central

    Eisenbarth, Ingrid; Beyer, Kim; Krone, Winfrid; Assum, Günter

    2000-01-01

    Summary Neurofibromatosis type 1 (NF1), a common autosomal dominant disorder caused by mutations of the NF1 gene, is characterized by multiple neurofibromas, pigmentation anomalies, and a variety of other possible complications, including an increased risk of malignant neoplasias. Tumorigenesis in NF1 is believed to follow the two-hit hypothesis postulated for tumor-suppressor genes. Loss of heterozygosity (LOH) has been shown to occur in NF1-associated malignancies and in benign neurofibromas, but only few of the latter yielded a positive result. Here we describe a systematic approach of searching for somatic inactivation of the NF1 gene in neurofibromas. In the course of these studies, two new intragenic polymorphisms of the NF1 gene, a tetranucleotide repeat and a 21-bp duplication, could be identified. Three tumor-specific point mutations and two LOH events were detected among seven neurofibromas from four different NF1 patients. Our results suggest that small subtle mutations occur with similar frequency to that of LOH in benign neurofibromas and that somatic inactivation of the NF1 gene is a general event in these tumors. The spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variable expressivity of the NF1 phenotype. PMID:10677298

  18. Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2

    PubMed Central

    Chan, Chi-Chao; Koch, Christian A; Kaiser-Kupfer, Muriel I; Parry, Dilys M; Gutmann, David H; Zhuang, Zhengping; Vortmeyer, Alexander O

    2008-01-01

    Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non-informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients. PMID:12210058

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

    PubMed Central

    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

    2015-01-01

    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. PMID:25293717

  20. Nam Con Son Basin

    SciTech Connect

    Tin, N.T.; Ty, N.D.; Hung, L.T.

    1994-07-01

    The Nam Con Son basin is the largest oil and gas bearing basin in Vietnam, and has a number of producing fields. The history of studies in the basin can be divided into four periods: Pre-1975, 1976-1980, 1981-1989, and 1990-present. A number of oil companies have carried out geological and geophysical studies and conducted drilling activities in the basin. These include ONGC, Enterprise Oil, BP, Shell, Petro-Canada, IPL, Lasmo, etc. Pre-Tertiary formations comprise quartz diorites, granodiorites, and metamorphic rocks of Mesozoic age. Cenozoic rocks include those of the Cau Formation (Oligocene and older), Dua Formation (lower Miocene), Thong-Mang Cau Formation (middle Miocene), Nam Con Son Formation (upper Miocene) and Bien Dong Formation (Pliocene-Quaternary). The basement is composed of pre-Cenozoic formations. Three fault systems are evident in the basin: north-south fault system, northeast-southwest fault system, and east-west fault system. Four tectonic zones can also be distinguished: western differentiated zone, northern differentiated zone, Dua-Natuna high zone, and eastern trough zone.

  1. Posterior-only spinal fusion without rib head resection for treating type I neurofibromatosis with intra-canal rib head dislocation

    PubMed Central

    Sun, Dong; Dai, Fei; Liu, Yao Yao; Xu, Jian-Zhong

    2013-01-01

    OBJECTIVES: Patients with Type I neurofibromatosis scoliosis with intra-canal rib head protrusion are extremely rare. Current knowledge regarding the diagnosis and treatment for this situation are insufficient. The purpose of this study is to share our experience in the diagnosis and surgical treatments for such unique deformities. METHODS: Six patients with Type I neurofibromatosis scoliosis with rib head dislocation into the spinal canal were diagnosed at our institution. Posterior instrumentation and spinal fusion without intra-canal rib head resection via a posterior-only approach was performed for deformity correction and rib head extraction. The efficacy and outcomes of the surgery were evaluated by measurements before, immediately and 24 months after the surgery using the following parameters: coronal spinal Cobb angle, apex rotation and kyphosis of the spine and the intra-canal rib head position. Post-operative complications, surgery time and blood loss were also evaluated. RESULTS: Patients were followed up for at least 24 months post-operatively. The three dimensional spinal deformity was significantly improved and the intra-canal rib head was significantly extracted from the canal immediately after the surgery. At follow-up 24 months after surgery, solid fusions were achieved along the fusion segments, and the deformity corrections and rib head positions were well maintained. There were no surgery-related complications any time after the surgery. CONCLUSIONS: Systematic examinations are needed to identify patients with Type I neurofibromatosis scoliosis with rib head dislocation into the canal who can be treated by posterior-only spinal fusion without rib head resection. PMID:24473510

  2. Primary parapharyngeal and skull base synovial sarcoma in a 13-year-old boy with neurofibromatosis radiologically misdiagnosed as a benign lesion.

    PubMed

    Zahir, Shokouh Taghipour; Sharahjin, Naser Sefidrokh; Dadgarnia, Mohammad Hossein

    2013-06-03

    Synovial sarcoma is a rare form of malignant tumour and accounting approximately for 8% of all soft tissue sarcomas. Head and neck synovial sarcomas are uncommon and parapharyngeal space involvement is extremely rare. We report a case of synovial sarcoma in the parapharyngeal space of a 13-year-old boy with a history of neurofibromatosis presented with odynophagia, ptosis and left submandibular mass. The lesion extended from retrostyloid parapharyngeal space to the skull base and foramen jugular superiorly. The first clinical and radiological impressions were carotid jugular related tumours such as schwannoma and paraganglioma.

  3. Unilateral gynaecomastia in a 16-month-old boy with neurofibromatosis type 1 - case report and brief review of the literature.

    PubMed

    Friedrich, Reinhard E; Hagel, Christian; Mautner, Victor-Felix

    2015-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that shows high penetrance with a wide variability in the phenotype. Prepubertal enlargement of the breast in male subjects affected by this condition is well known, but rarely reported. The present case report describes diagnosis and therapy of unilateral gynaecomastia in a toddler showing integumental stigmata of NF1. Furthermore, the report provides a brief review of the literature concerning this finding in NF1. According to this review, the present case appears to be one of the youngest NF1-affected males affected by gynaecomastia that has been reported.

  4. Unilateral gynaecomastia in a 16-month-old boy with neurofibromatosis type 1 – case report and brief review of the literature

    PubMed Central

    Friedrich, Reinhard E.; Hagel, Christian; Mautner, Victor-Felix

    2015-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that shows high penetrance with a wide variability in the phenotype. Prepubertal enlargement of the breast in male subjects affected by this condition is well known, but rarely reported. The present case report describes diagnosis and therapy of unilateral gynaecomastia in a toddler showing integumental stigmata of NF1. Furthermore, the report provides a brief review of the literature concerning this finding in NF1. According to this review, the present case appears to be one of the youngest NF1-affected males affected by gynaecomastia that has been reported. PMID:26668786

  5. A Phase 2 Trial on the Effect of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1)

    DTIC Science & Technology

    2014-10-01

    of Low-Dose versus High-Dose Vitamin D Supplementation on Bone Mass in Adults with Neurofibromatosis 1 (NF1) PRINCIPAL INVESTIGATOR: David...High-dose Vitamin D Supplementation on Bone Mass in Adults with 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0487 5c...processes have taken more time than anticipated in the Statement of Work. This study has received an IND from the FDA to use high-dose vitamin D in the

  6. Neurofibromatosis type 1 and pregnancy: The transformation of a nodular to cystic neurofibroma in the cervical region

    PubMed Central

    Ramos-Zúñiga, Rodrigo; Saldaña-Koppel, Daniel Alexander

    2015-01-01

    Background: The peripheral hallmarks of neurofibromatosis type 1 (NF1) are Café au lait and solid nodular neurofibromas. The morphological behavior of these lesions could be susceptible to modification during pregnancy. The present case report describes a case of cystic transformation of a nodular neurofibroma, with progressive growth and mass effect in the anterior cervical region, which was surgically resolved without any complications. Case Description: A 33-year-old female patient with a known personal history of NF1, with annual control of the peripheral neurofibromas and cerebral and spinal magnetic resonance imaging follow-ups. Under genetic counseling, she decides to get pregnant following all the medical advises. Once the pregnancy is confirmed, she starts to notice the growth of one of them adjacent to the left cervical region. Such neurofibroma presented with the progressive gradual increase and in the last month, she presented dysphagia, dysphonia, and postural pain localized by the mass effect. Once the pregnancy concluded, the microsurgical approach was scheduled for resection of the lesion, where a cystic mass was found within the walls of the neurofibroma. The resection was uneventful. Conclusion: The transformation of a nodular to cystic neurofibroma during pregnancy is a very rare presentation, which may exacerbate the clinical symptomatology depending on the topography of the lesion due to the mass effect it may create. This condition may alert to the recommendations and vigilance in patients with NF1, who are pregnant or are planning on a future pregnancy. The neurosurgical resolution in this region is safe and beneficial. PMID:26605110

  7. Healthcare transition in patients with rare genetic disorders with and without developmental disability: neurofibromatosis 1 and Williams-Beuren syndrome.

    PubMed

    Van Lierde, Andrea; Menni, Francesca; Bedeschi, Maria Francesca; Natacci, Federica; Guez, Sophie; Vizziello, Paola; Costantino, Maria Antonella; Lalatta, Faustina; Esposito, Susanna

    2013-07-01

    There are between 5,000 and 8,000 distinct rare diseases (RDs) affecting 6-8% of the population, most of which are caused by genetic defects. Many are highly complex, childhood-onset, multi-system disorders that are often associated with developmental disability, and require lifelong, highly specialized care and support. As larger numbers of children with previously fatal RDs survive into adulthood, they encounter significant challenges in transitioning from family-centered, developmentally focused, multidisciplinary pediatric care to a less supportive adult healthcare system that is often unfamiliar with these conditions. This paper discusses the challenges of the transition from pediatric to adult health care in two groups of patients with multisystem genetic RDs (neurofibromatosis 1 [NF1] and Williams-Beuren syndrome [WBS]), and analyzes strategies for making the process easier for patients with and without developmental disabilities. Our findings show that there are still no guidelines in national healthcare programs on how to transition RD adolescents with and without developmental disabilities, and only a few pediatric centers have implemented the elements of transition in their general practice. Evidence regarding programs to facilitate transition is inconclusive and the transition from pediatric medicine to adult medicine for RDs remains a major challenge. However, transition requires both time and personnel, which are difficult to find in periods of fiscal austerity. Nevertheless, we should strongly advocate for governments investing more into transition infrastructure or they will face increased long-term social and economic costs due to poor treatment compliance, disengagement from services, increased genetic risks, and higher rates of disease-related complications.

  8. Heat hyperalgesia and mechanical hypersensitivity induced by calcitonin gene-related peptide in a mouse model of neurofibromatosis.

    PubMed

    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.

  9. Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study

    PubMed Central

    2012-01-01

    Objective To identify clinical characteristics associated with internal neurofibromas in children with NF1, as a means of ensuring the early identification of patients at high risk for malignant peripheral nerve-sheath tumors developed from preexisting internal neurofibromas. Patients and methods We used data from two NF1 populations, in France and North America, respectively. The French database comprised 1083 patients meeting NIH diagnostic criteria for NF1 and the Neurofibromatosis Institute Database of North America comprised 703 patients. Patients younger than 17 years of age were eligible for our study if they had been evaluated for internal neurofibromas using computed tomography and/or magnetic resonance imaging. Clinical characteristics associated with internal neurofibromas by univariate analysis (P ≤ 0.15) were entered into a multiple logistic regression model after checking for potential interactions and confounding. Multiple imputation was used for missing values. Results Among the 746 children in the two databases, 357 (48%) met our inclusion criteria. Their mean age was 7.7 ± 5.0 years and there were 192 (53.8%) males. Internal neurofibromas were present in 35 (9.8%) patients. Internal neurofibromas developed earlier in females than in males and their prevalence increased during adolescence. Factors independently associated with internal neurofibromas were age (OR = 1.16 [1.07-1.27]), xanthogranulomas (OR = 5.85 [2.18-15.89]) and presence of both subcutaneous and plexiform neurofibromas (OR = 6.80 [1.52-30.44]). Conclusions Several easily recognizable clinical characteristics indicate a high risk of internal neurofibromas in children with NF1 and, therefore, a need for very close monitoring. PMID:22943186

  10. Neurofibromatosis type 1 and Chiari type 1 malformation: A case report and literature review of a rare association

    PubMed Central

    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

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

    PubMed

    Pemov, Alexander; Sung, Heejong; Hyland, Paula L; Sloan, Jennifer L; Ruppert, Sarah L; Baldwin, Andrea M; Boland, Joseph F; Bass, Sara E; Lee, Hyo Jung; Jones, Kristine M; Zhang, Xijun; Mullikin, James C; Widemann, Brigitte C; Wilson, Alexander F; Stewart, Douglas R

    2014-10-01

    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.

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

    PubMed Central

    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.

    2016-01-01

    ABSTRACT 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. PMID:27482814

  13. Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis

    PubMed Central

    Pemov, Alexander; Sung, Heejong; Hyland, Paula L.; Sloan, Jennifer L.; Ruppert, Sarah L.; Baldwin, Andrea M.; Boland, Joseph F.; Bass, Sara E.; Lee, Hyo Jung; Jones, Kristine M.; Zhang, Xijun; Mullikin, James C.; Widemann, Brigitte C.; Wilson, Alexander F.; Stewart, Douglas R.

    2014-01-01

    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. PMID:25329635

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  17. Evolution and origin of merlin, the product of the Neurofibromatosis type 2 (NF2) tumor-suppressor gene

    PubMed Central

    Golovnina, Kseniya; Blinov, Alexander; Akhmametyeva, Elena M; Omelyanchuk, Leonid V; Chang, Long-Sheng

    2005-01-01

    Background Merlin, the product of the Neurofibromatosis type 2 (NF2) tumor suppressor gene, belongs to the ezrin-radixin-moesin (ERM) subgroup of the protein 4.1 superfamily, which links cell surface glycoproteins to the actin cytoskeleton. While merlin's functional activity has been examined in mammalian and Drosophila models, little is understood about its evolution, diversity, and overall distribution among different taxa. Results By combining bioinformatic and phylogenetic approaches, we demonstrate that merlin homologs are present across a wide range of metazoan lineages. While the phylogenetic tree shows a monophyletic origin of the ERM family, the origin of the merlin proteins is robustly separated from that of the ERM proteins. The derivation of merlin is thought to be in early metazoa. We have also observed the expansion of the ERM-like proteins within the vertebrate clade, which occurred after its separation from Urochordata (Ciona intestinalis). Amino acid sequence alignment reveals the absence of an actin-binding site in the C-terminal region of all merlin proteins from various species but the presence of a conserved internal binding site in the N-terminal domain of the merlin and ERM proteins. In addition, a more conserved pattern of amino acid residues is found in the region containing the so-called "Blue Box," although some amino acid substitutions in this region exist in the merlin sequences of worms, fish, and Ciona. Examination of sequence variability at functionally significant sites, including the serine-518 residue, the phosphorylation of which modulates merlin's intra-molecular association and function as a tumor suppressor, identifies several potentially important sites that are conserved among all merlin proteins but divergent in the ERM proteins. Secondary structure prediction reveals the presence of a conserved α-helical domain in the central to C-terminal region of the merlin proteins of various species. The conserved residues and

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

    PubMed

    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 (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 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

  19. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

    PubMed

    Ruggieri, M; Praticò, A D; Serra, A; Maiolino, L; Cocuzza, S; Di Mauro, P; Licciardello, L; Milone, P; Privitera, G; Belfiore, G; Di Pietro, M; Di Raimondo, F; Romano, A; Chiarenza, A; Muglia, M; Polizzi, A; Evans, D G

    2016-10-01

    Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed

  20. A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals

    SciTech Connect

    Bourn, D.; Carter, S.A.; Goodship, J.; Strachan, T. ); Evans, G.R.; Coakham, H.

    1994-07-01

    The authors have sought mutations in the recently identified neurofibromatosis type 2 (NF2) tumor-suppressor gene in a large panel of NF2 patients, using PCR-based SSCP and heteroduplex analysis, followed by cloning and sequencing of appropriate PCR products. Two unrelated NF2 patients were found to have identical nonsense mutations caused by a C-to-T transition in a CpG dinucleotide that is a potential mutational hot spot in the NF2 tumor-suppressor gene. Unexpectedly, the two individuals had widely different clinical phenotypes, representing the severe Wishart and mild Gardner clinical subtypes. Analysis of DNA samples from different tissues of the mildly affected patient suggests that he is a somatic mosaic for the mutation. 26 refs., 3 figs.

  1. Tandem duplication within a Neurofibromatosis type I (NFI) gene exon in a family with features of Watson syndrome and Noonan syndrome

    SciTech Connect

    Tassabehji, M.; Strachan, T.; Colley, A.; Donnai, D.; Harris, R.; Thakker, N. ); Sharland, M )

    1993-07-01

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or the phenotypes arise from mutations in very closely linked genes. Here the authors provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. 31 refs., 2 figs.

  2. Reconstruction of Sphenoid Wing Dysplasia with Pulsating Exophthalmos in a Case of Neurofibromatosis Type 1 Supported by Intraoperative Navigation Using a New Skull Reference System.

    PubMed

    Friedrich, Reinhard E; Heiland, Max; Kehler, Uwe; Schmelzle, Rainer

    2003-11-01

    A patient with neurofibromatosis type 1 had pulsating exophthalmos of the right eye with diplopia resulting from severe dysplasia of the sphenoid bone and consecutive herniation of the right temporal lobe. The right orbital tectum was reconstructed with titanium mesh and iliac spongiosa via a lateral orbitotomy using intraoperative navigation. For intraoperative referencing a cortical fixed-reference system and a skin scanning laser device were used. Postoperatively, the diplopia was reduced, but the patient asked for further treatment and the procedure was repeated 6 months later. Intraoperatively, the previously implanted titanium mesh was deformed and most of the transplanted bone was resorbed, probably because of pressure. A more extended mesh was implanted and iliac spongiosa was placed on both sides. Intraoperative navigation was used during both procedures. The adverse effects of diplopia were minimized and follow-up computed tomography after seven months confirmed that the bone graft was in place.

  3. An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots, Freckling, and Neurofibromas. An Update. Part I. Dermatological Clinical Criteria Diagnostic of the Disease.

    PubMed

    Hernández-Martín, A; Duat-Rodríguez, A

    2016-01-01

    Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists, who are generally the first physicians to suspect its diagnosis. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still mainly based on clinical observations and the diagnostic criteria of the National Institute of Health, dating from 1988. Cutaneous manifestations are particularly important because café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas comprise 3 of the 7 clinical diagnostic criteria. However, café-au-lait spots and freckling can also be present in other diseases. These manifestations are therefore not pathognomonic and are insufficient for definitive diagnosis in the early years of life. NF1 is a multisystemic disease associated with a predisposition to cancer. A multidisciplinary follow-up is necessary and dermatologists play an important role.

  4. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome.

    PubMed Central

    Tassabehji, M; Strachan, T; Sharland, M; Colley, A; Donnai, D; Harris, R; Thakker, N

    1993-01-01

    Type 1 neurofibromatosis (NF1), Watson syndrome (WS), and Noonan syndrome (NS) show some overlap in clinical manifestations. In addition, WS has been shown to be linked to markers flanking the NF1 locus and a deletion at the NF1 locus demonstrated in a WS patient. This suggests either that WS and NF1 are allelic or that phenotypes arise from mutations in very closely linked genes. Here we provide evidence for the former by demonstrating a mutation in the NF1 gene in a family with features of both WS and NS. The mutation is an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene. Unlike the mutations previously described in classical NF1, which show a preponderance of null alleles, the mutation in this family would be expected to result in a mutant neurofibromin product. Images Figure 1 Figure 2 PMID:8317503

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

    PubMed

    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.

  6. Association of tumor location, extent of resection, and neurofibromatosis status with clinical outcomes for 221 spinal nerve sheath tumors.

    PubMed

    Safaee, Michael; Parsa, Andrew T; Barbaro, Nicholas M; Chou, Dean; Mummaneni, Praveen V; Weinstein, Philip R; Tihan, Tarik; Ames, Christopher P

    2015-08-01

    OBJECT Intradural extramedullary spine tumors represent two-thirds of all primary spine neoplasms. Approximately half of these are peripheral nerve sheath tumors, mainly neurofibromas and schwannomas. Given the rarity of this disease and, thus, the limited analyses of clinical outcomes, the authors examined the association of tumor location, extent of resection, and neurofibromatosis (NF) status with clinical outcomes. METHODS Patients were identified through a search of the University of California, San Francisco, neuropathology database and a separate review of current procedural terminology codes. Data recorded included patient age, patient sex, clinical presentation, presence of NF, tumor type, tumor location, extent of resection (gross-total resection [GTR] or subtotal resection [STR]), and clinical follow-up. RESULTS Of 221 tumors in 199 patients (mean age 45 years), 53 were neurofibromas, 163 were schwannomas, and 5 were malignant peripheral nerve sheath tumors. The most common presenting symptom was spinal pain (76%), followed by weakness (36%) and sensory abnormalities (34%). Mean symptom duration was 16 months. In terms of spinal location, neurofibromas were more common in the cervical spine (74% vs 27%, p < 0.001), and schwannomas were more common in the thoracic and lumbosacral spine (73% vs 26%, p < 0.001). Rates of GTR were lower for neurofibromas than schwannomas (51% vs 83%, p < 0.001), regardless of location. Rates of GTR were lower for cervical (54%) than thoracic (90%) and lumbosacral (86%) lesions (p < 0.001). NF was associated with lower rates of GTR among all tumors (43% vs 86%, p < 0.001). The mean follow-up time was 32 months. Recurrence/progression was more common for neurofibromas than schwannomas (17% vs 7%, p = 0.03), although the mean time to recurrence/progression did not differ according to tumor type (45 vs 53 months, p = 0.63). As expected, GTR was associated with lower recurrence rates (4% vs 22%, p < 0.001). According to

  7. Neurofibromatosis (For Parents)

    MedlinePlus

    ... Looking for Health Lessons? Visit KidsHealth in the Classroom What Other Parents Are Reading Your Child's Development ( ... at least ½ inch in diameter (roughly the size of a dime), a doctor will look for ...

  8. Learning about Neurofibromatosis

    MedlinePlus

    ... 000 births. NF2, also referred to as bilateral acoustic NF, central NF or vestibular NF, occurs less ... nerves. These tumors often cause pressure on the acoustic nerves, which result in hearing loss. Hearing loss ...

  9. Breast cancer and other neoplasms in women with neurofibromatosis type 1: a retrospective review of cases in the Detroit metropolitan area.

    PubMed

    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.

  10. Brief Report: The Prevalence of Neurofibromatosis Type 1 among Children with Autism Spectrum Disorder Identified by the Autism and Developmental Disabilities Monitoring Network.

    PubMed

    Bilder, Deborah A; Bakian, Amanda V; Stevenson, David A; Carbone, Paul S; Cunniff, Christopher; Goodman, Alyson B; McMahon, William M; Fisher, Nicole P; Viskochil, David

    2016-10-01

    Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous disorder associated with neurodevelopmental disorders including autism spectrum disorder (ASD). The frequency of ASD/NF1 co-occurrence has been subject to debate since the 1980s. This relationship was investigated in a large population-based sample of 8-year-old children identified with ASD (N = 12,271) by the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring (ADDM) Network. Twenty-two (1-in-558) children with ASD had diagnosed NF1, exceeding NF1 general population estimates by four to five fold. Children with ASD/NF1 versus ASD without NF1 were significantly less likely to receive a community-based ASD diagnosis (p = 0.04) and understand non-verbal communication (p = 0.001). These findings underscore the importance of including social-communication ability among relevant developmental concerns in children with NF1.

  11. Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system.

    PubMed

    Brossier, Nicole M; Carroll, Steven L

    2012-05-01

    Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: (1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; (2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; (3) how the tumor microenvironment contributes to neoplasia; (4) what additional mutations contribute to neurofibroma-MPNST progression; (5) what role different neurofibromin-regulated Ras proteins play in this process and (6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.

  12. Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

    PubMed

    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.

  13. Radiosensitivity of fibroblasts obtained from a cafe-au-lait spot and normal-appearing skin of a patient with neurofibromatosis (NF-6)

    SciTech Connect

    Hannan, M.A.; Smith, B.P.; Sigut, D.; Sackey, K. )

    1990-07-15

    Fibroblast cells derived from a cafe-au-lait spot and normal-appearing skin of a neurofibromatosis (NF-6) patient were studied for radiosensitivity in comparison with two normal cell lines used as controls. No difference in radiosensitivity was observed between the patient's cell lines and the controls using acute gamma-irradiation. However, a markedly increased radiosensitivity of the fibroblasts obtained from the patient's skin of normal appearance was demonstrated after chronic gamma-irradiation. The cells from the cafe-au-lait spot showed intermediate sensitivity to chronic irradiation as compared with the control cell lines and the fibroblasts derived from the normal skin of the patient. These results showed the usefulness of chronic irradiation in detecting increased cellular radiosensitivity which may result from a unique DNA repair defect in an NF patient. We suggest that enhanced genetic changes in radiosensitive NF patients may lead to formation of cafe-au-lait lesions and certain tumors. Such a transformation may be associated with production of radiotolerant cells.

  14. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    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. PMID:26585233

  15. Development of the pediatric quality of life inventory neurofibromatosis type 1 module items for children, adolescents and young adults: qualitative methods.

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  19. High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report

    PubMed Central

    Mikirova, Nina; Hunnunghake, Ronald; Scimeca, Ruth C.; Chinshaw, Charles; Ali, Faryal; Brannon, Chris; Riordan, Neil

    2016-01-01

    Patient: Male, 1 Final Diagnosis: Optic glioma Symptoms: Visual problems Medication: — Clinical Procedure: Intravenous vitamin C Specialty: Oncology Objective: Unusual clinical course Background: In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma. Case Report: We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7–15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment. Conclusions: This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment. PMID:27773919

  20. A genetic study of neurofibromatosis type 1 (NF1) in south-western Ontario. II. A PCR based approach to molecular and prenatal diagnosis using linkage.

    PubMed Central

    Rodenhiser, D I; Ainsworth, P J; Coulter-Mackie, M B; Singh, S M; Jung, J H

    1993-01-01

    Neurofibromatosis type 1 (NF1) is a common, autosomal dominant genetic disorder with a variety of highly variable symptoms including cutaneous manifestations (such as café au lait spots), Lisch nodules, plexiform neurofibromas, skeletal abnormalities, an increased risk for malignancy, and the development of learning disabilities. The wide clinical variability of expression of the disease phenotype and high (spontaneous) mutation rate of the NF1 gene indicate that careful clinical examination of patients and family members is necessary to provide an accurate diagnosis of the disease. Since very few NF1 mutations have been identified, and with the apparent lack of a predominant mutation in this large, highly mutable gene, molecular diagnosis of NF1 will continue to be based on haplotypes using linkage analysis. Here we report our experiences while providing a molecular diagnostic service for NF1 in the ethnically diverse region of south-western Ontario. Molecular diagnoses with at least one informative probe/enzyme combination are reported for 19 families including two families requesting prenatal diagnosis for NF1. We have augmented the classical Southern based approach to linkage analysis with the use of PCR based assays for molecular linkage. Furthermore, criteria have been established in our laboratory for executing molecular linkage based on heterozygosity values, recombination fractions, and the use of intragenic probes/markers. Images PMID:8320697

  1. Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially- and Temporally-Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth

    PubMed Central

    Simmons, Grant W.; Pong, Winnie W.; Emnett, Ryan J.; White, Crystal R.; Gianino, Scott M.; Rodriguez, Fausto J.; Gutmann, David H.

    2011-01-01

    While carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression is heavily influenced by the local microenvironment. Previous studies from our laboratory have employed 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 employed CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times following ganciclovir (GCV) administration. GCV-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. PMID:21157378

  2. Aspergilosis cervical con diseminación al sistema nervioso central. Presentación de un caso y revisión de bibliografía

    PubMed Central

    Vergara, Guillermo Enrique; Roura, Natalia; del Castillo, Marcelo; Mora, Andrea; Alcorta, Santiago Condomi; Mormandi, Rubén; Cervio, Andrés; Salvat, Jorge

    2015-01-01

    Introducción: la Aspergilosis Invasiva (AI) del Sistema Nervioso Central (SNC) es infrecuente y ocurre generalmente en pacientes inmunocomprometidos. Puede presentarse con cuadros de meningitis, aneurismas micóticos, infartos o abscesos. Es una infección con pronóstico reservado y puede afectar el SNC de forma primaria o secundaria a partir de un foco que se disemina por vía hematógena. Presentamos el caso de un paciente con AI con invasión primaria a nivel óseo y diseminación posterior al cerebro. Caso clínico: Paciente masculino de 25 años con diagnóstico de leucemia linfática aguda en tratamiento quimioterápico que presentó neumonitis por metotrexate por lo que inicia tratamiento con corticoides. Posteriormente agregó cervicalgia y con el diagnóstico de osteomielitis cervical se realiza punción bajo tomografía computada (TC) sin aislarse gérmenes. Se colocó Halo Vest e inició tratamiento antibiótico empírico. Posteriormente presentó afasia de expresión secundaria a lesión frontal izquierda. Se realizó evacuación de absceso cerebral aislando A. fumigatus. El tratamiento antibiótico específico posterior permitió una buena respuesta clínica y radiológica. Conclusión: La presencia de lesiones en el SNC de pacientes inmunocomprometidos debe incluir a las micosis como diagnóstico diferencial. La evacuación quirúrgica permite llegar rápidamente al diagnóstico mejorando la respuesta posterior al tratamiento antibiótico. Para evaluar la respuesta terapéutica y posibles recaídas se debe realizar un seguimiento periódico clínico radiológico. Palabras clave: Aspergilosis cerebral; Aspergilosis cervical; Aspergilosis invasiva; Voriconazol. PMID:26600985

  3. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989.

    PubMed

    Evans, D Gareth R; O'Hara, Catherine; Wilding, Anna; Ingham, Sarah L; Howard, Elizabeth; Dawson, John; Moran, Anthony; Scott-Kitching, Vilka; Holt, Felicity; Huson, Susan M

    2011-11-01

    Neurofibromatosis 1 (NF1) is a comparatively common autosomal dominant disorder. However, relatively few studies have assessed lifetime risk; and information about the effect of NF1 on mortality remains uncertain. NF1 patients were identified using The North West regional family Genetic Register, which covers the 4.1 million people living in North West England, including the regions of Greater Manchester, Cheshire and Cumbria. Data relating to tumours and malignancies were obtained from The North West Cancer Intelligence Service. Death data for the general North West population were obtained from the Office of National Statistics. We identified 1186 individuals with NF1, of whom 1023 lived within the strict regional boundaries (constituting a region of North West England bound by The Pennines to the east and Irish Sea to the west, but excluding the conurbation of Liverpool (Merseyside) and the Wirral peninsula) and 131 had died. MPNST and glioma were found to be the two most common causes of reduced life expectancy among NF1 patients. In Kaplan-Meier analyses the median survival for NF1 patients was shown to be 71.5 years, with women living ∼7.4 years longer than men. On average both men and women lived ∼8 years less than their counterparts in the general population. Reduction in life expectancy for NF1 patients was found to be much lower (8 years) than the previously estimated 15-year decrease. Limitations relating to the underreporting of NF1 on death certificates were once again highlighted and should be considered in future investigations.

  4. Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p.

    PubMed

    Lee, Hong; Hwang, Su Jin; Kim, Hye Ree; Shin, Chang Hoon; Choi, Kyung Hee; Joung, Je-Gun; Kim, Hyeon Ho

    2016-04-01

    Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor derived from non-neuronal glial cells. Neurofibromatosis 2 (NF2) protein, also termed as merlin, is a well-known tumor suppressor; however, the molecular mechanism underlying this effect has not yet been fully defined. To investigate the role of NF2 in the invasiveness of GBM, we used two GBM cell lines: NF2-expressing T98G cells and NF2-deficient A172 cells. Knockdown of NF2 increased the invasiveness of T98G cells, whereas NF2-overexpressing A172 cells showed decreased invasive activity. Moreover, re-expression of NF2 reversed the high invasiveness of NF2-silenced T98G cells, indicating that NF2 negatively regulates GBM invasiveness. We further found that the NF2-mediated regulation of invasiveness was dependent on YAP and TEAD2 expression levels. NF2 also controlled the expression of YAP targets, including cysteine-rich angiogenic inducer 61 (CYR61/CCN1), by regulating the nuclear localization of YAP. Silencing of CYR61/CCN1 blocked the increased invasiveness of T98G cells, suggesting that CYR61/CCN1 is required for NF2-mediated invasiveness. Through microRNA microarray analysis, we found that NF2 negatively regulates the expression of miR-296-3p. Overexpression of miR-296-3p suppressed the expression of STAT5A, induced the phosphorylation of STAT3 by downregulating SOCS2, and increased the invasiveness of T98G cells. Taken together, we demonstrate that NF2 negatively controls the invasiveness of GBM through YAP-dependent induction of CYR61/CCN1 and miR-296-3p.

  5. A man who inherited his SRY gene and Leri-Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father.

    PubMed

    Wei, F; Cheng, S; Badie, N; Elder, F; Scott, C; Nicholson, L; Ross, J L; Zinn, A R

    2001-09-01

    We report on a man with neurofibromatosis type 1 (NF1) and Leri-Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 +,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence < 300 kb from PABX, suggesting that the deletion encompassed only pseudoautosomal sequences. Replication studies indicated that the normal X and the dic(X;Y) were randomly inactivated in the proband's lymphocytes. LWD in the proband and his mother was explained by SHOX haploinsufficiency. The mother's female phenotype was most likely due to 45,X mosaicism. This family segregating Mendelian and chromosomal disorders illustrates extreme sex chromosome variation compatible with normal male and female sexual differentiation. The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency.

  6. Sensitive detection of deletions of one or more exons in the neurofibromatosis type 2 (NF2) gene by multiplexed gene dosage polymerase chain reaction.

    PubMed

    Diebold, Ruth; Bartelt-Kirbach, Britta; Evans, D Gareth; Kaufmann, Dieter; Hanemann, C Oliver

    2005-02-01

    Mutation detection in the neurofibromatosis type 2 (NF2) gene is challenging because when combining mutation detection methods such as single-strand conformational polymorphism and heteroduplex analysis, denaturing gradient gel electrophoresis, and direct sequencing of aberrant polymerase chain reaction (PCR) fragments only 30 to 60% of the constitutional mutations are detected. Because large deletions and complete chromosome rearrangements are also described methods such as microarray-comparative genomic hybridization and fluorescence in situ hybridization are also used. The one type of mutation often missed corresponds to deletions encompassing one or few exons. To detect this type we have developed a swift and reliable method. We perform a gene dosage analysis with two fluorescent multiplex PCR assays that amplify 15 of the 17 NF2 exons. The labeled PCR products are quantified and gene dose is calculated with respect to controls. We tested the reliability of this method with DNA from eight NF2 patients with known heterozygous NF2 deletions, eight controls and four unknown NF2 patients. In all of the patients with known heterozygous deletions we found in several exons a reduction of gene dosage to 50 to 69%. In one NF2 patient with previously unknown mutation and a severe phenotype we found the gene dosage of two exons reduced by 50% indicating a deletion of these two exons on one allele. This finding was validated by reverse transcriptase-PCR on fibroblast and schwannoma cell cultures of this patient and cDNA sequencing. Our gene dosage assay will detect deletions of one or more exons as well as gross deletions of the whole coding region of the gene. It can complement the existing screening methods because it is faster and easier.

  7. [Bariatric surgery in adults: variables that facilitate and hinder weight loss from pacients perspective].

    PubMed

    Lecaros-Bravo, Javiera; Cruzat-Mandich, Claudia; Díaz-Castrillón, Fernanda; Moore-Infante, Catalina

    2015-04-01

    Introducción: La obesidad se ha convertido en un problema de salud pública a nivel mundial. Asociado a esto, las cirugías bariátricas han ido en progresivo aumento, dada su efectividad en la baja de peso a corto plazo. Sin embargo, se ha visto que existe un alto porcentaje de reganancia de peso a partir del tercer año post cirugía y existen pocos estudios de seguimiento de estos pacientes. Objetivos: Describir los facilitadores y obstaculizadores de la pérdida de peso, desde la perspectiva de adultos que han sido sometidos a cirugía bariátrica. Métodos: Se utilizó un enfoque cualitativo, descriptivo, basado en la Teoría Fundamentada. Se realizaron entrevistas en profundidad y los datos se analizaron a través de codificación abierta. La muestra estuvo compuesta por 8 mujeres y 3 hombres adultos, intervenidos en clínicas privadas. Resultados: Se generaron cinco categorías de análisis: (1) variables que favorecen la pérdida de peso post cirugía bariátrica, (2) variables que dificultan la pérdida y mantención de peso post cirugía, (3) evaluación de los resultados de la cirugía bariátrica, (4) problematización de la obesidad, y (5) relación con la comida. Discusión: Los principales hallazgos indican que el fracaso y el éxito en la pérdida de peso post cirugía se encuentra asociado a la posibilidad de tener una red de apoyo emocional y social, así como a la posibilidad de comprender y modificar el rol de la comida como mecanismo de regulación emocional.

  8. Genetic and Functional Studies Implicate Synaptic Overgrowth and Ring Gland cAMP/PKA Signaling Defects in the Drosophila melanogaster Neurofibromatosis-1 Growth Deficiency

    PubMed Central

    Walker, James A.; Gouzi, Jean Y.; Long, Jennifer B.; Huang, Sidong; Maher, Robert C.; Xia, Hongjing; Khalil, Kheyal; Ray, Arjun; Van Vactor, David; Bernards, René; Bernards, André

    2013-01-01

    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 1st and 2nd 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 give rise

  9. Cephalometry in adults and children with neurofibromatosis type 1: implications for the pathogenesis of sphenoid wing dysplasia and the “NF1 facies”

    PubMed Central

    Cung, Winnie; Friedman, Laura; Khan, Nicholas E.; Romberg, Elaine E.; Gardner, Pamela J.; Bassim, Carol W.; Baldwin, Andrea M.; Widemann, Brigitte C.; Stewart, Douglas R.

    2015-01-01

    Background Neurofibromatosis type 1 (NF1) is a common, autosomal dominant tumor-predisposition disorder that arises secondary to mutations in the tumor suppressor gene NF1. Cephalometry is an inexpensive, readily available and non-invasive technique that is under-utilized in studying the NF1 craniofacial phenotype. An analysis of NF1 cephalometry was first published by Heervä et al. in 2011. We expand here on that first investigation with a larger cohort of adult and pediatric patients affected with NF1 and sought objective insight into the NF1 facies, said to feature hypertelorism and a broad nasal base, from cephalometric analysis. Methods We obtained cephalograms from 101 patients with NF1 (78 adults and 23 children) from two NF1 protocols at the National Institutes of Health. Each subject had an age-, gender- and ethnicity-matched control. We used Dolphin software to make the cephalometric measurements. We assessed the normality of differences between paired samples using the Shapiro-Wilk test and evaluated the significance of mean differences using paired t-tests and adjusted for multiple testing. We explored the relationship between the cephalometric measurements and height, head circumference and interpupillary distance. Results In this dataset of American whites with NF1, we confirmed in a modestly larger sample many of the findings found by Heerva et al. in an NF1 Finnish cohort. We found a shorter maxilla, mandible, cranial base, (especially anteriorly, p = 0.0001) and diminished facial height in adults, but not children, with NF1. Only one adult exhibited hypertelorism. Conclusions The cephalometric differences in adults arise in part from cranial base shortening and thus result in a shorter face, mid-face hypoplasia, reduced facial projection, smaller jaw, and increased braincase globularity. In addition, we suggest that NF1 sphenoid bone shortening, a common event, is consistent with an intrinsic NF1 bone cell defect, which renders the bone more

  10. Utility of 18F-FDG PET with a Semi-Quantitative Index in the Detection of Sarcomatous Transformation in Patients with Neurofibromatosis Type 1

    PubMed Central

    Combemale, Patrick; Valeyrie-Allanore, Laurence; Giammarile, Francesco; Pinson, Stephane; Guillot, Bernard; Goulart, Denis Mariano; Wolkenstein, Pierre; Blay, Jean Yves; Mognetti, Thomas

    2014-01-01

    Background Malignant peripheral nerve sheath tumors (MPNSTs) are a serious complications of neurofibromatosis type 1 associated with poor prognosis and deeper lesions can be difficult to diagnose. 18-FDG PET improves the detection of malignancies. However, the criteria for malignancy, notably the SUVmax threshold, are not standardized. Therefore, the aim of the study was to evaluate a semi-quantitative index for the reproducible detection of MPNST with FDG PET. Methods It is a multicenter retrospective study conducted between 2000 to 2012. All patients with NF1 referred for suspected MPNST underwent PET. Since SUVmax was not available until 2004 in our centers, we had to settle for the semi-quantitative method used at that time, the uptake ratio between the tumor and the normal liver (T/L ratio) with 1.5 as the cut-off for malignancy. When dedicated PET with SUVmax became available, the semi-quantitative analysis of PET images remained, along with SUVmax. Results 113 patients with 145 tumors were included. PET assessment revealed 65 suspected lesions with T/L >1.5 and among these, 40 were MPNSTs. 80 tumors were classified as non-suspicious, and 79 were benign. The 1.5 T/L cut-off had a negative predictive value (NPV) of 98,8% and a positive predictive value of 61,5%. The positive likelihood ratio (LR) was 4,059, the negative LR was 0,032 with 97% sensitivity and 76% specificity. Conclusions This study, which is among the largest published, confirms the utility of PET for detecting NF1-associated MPNSTs. A semi-quantitative index, the T/L ratio with a cut-off of 1.5, allowed sensitive and specific differentiation of malignant from benign tumors better than SUVmax. When T/L was <1.5, MPNSTs were ruled out with 98,8% NPV. When T/L was >1.5, there was a strong suspicion of malignancy. This semi-quantitative analytical method is as simple as SUVmax, but is more sensitive, more reproducible and non-user-dependent. PMID:24516522

  11. Metabolic Tumour Burden Measured by 18F-FDG PET/CT Predicts Malignant Transformation in Patients with Neurofibromatosis Type-1

    PubMed Central

    Van Der Gucht, Axel; Zehou, Ouidad; Djelbani-Ahmed, Soraya; Valeyrie-Allanore, Laurence; Ortonne, Nicolas; Brugières, Pierre; Wolkenstein, Pierre; Luciani, Alain; Rahmouni, Alain; Sbidian, Emilie; Itti, Emmanuel

    2016-01-01

    Background To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation. Methods This retrospective study included 49 patients (15–60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival. Results Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG ≤ 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; χ2 27.85; hazard ratio 13.27 [95% CI, 3.72–47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with χ2 ranging 14.41–19.12. The HIsuv index was not predictive of survival. Conclusion Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and

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

    PubMed

    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

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

    PubMed

    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

  14. Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells*

    PubMed Central

    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

    2013-01-01

    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

  15. Fibroadenoma and phyllodes tumors of anogenital mammary-like glands: a series of 13 neoplasms in 12 cases, including mammary-type juvenile fibroadenoma, fibroadenoma with lactation changes, and neurofibromatosis-associated pseudoangiomatous stromal hyperplasia with multinucleated giant cells.

    PubMed

    Kazakov, Dmitry V; Spagnolo, Dominic V; Stewart, Colin J; Thompson, Jane; Agaimy, Abbas; Magro, Gaetano; Bisceglia, Michele; Vazmitel, Marina; Kacerovska, Denisa; Kutzner, Heinz; Mukensnabl, Petr; Michal, Michal

    2010-01-01

    The authors present a series of 13 fibroepithelial neoplasms involving anogenital mammary-like glands, all occurring in 12 female patients, whose age at diagnosis ranged from 30 to 51 years (mean, 38 y; median, 42 y). All women presented with a solitary asymptomatic nodule in the vulva (n=8), perineum (n=2), or near the anus (n=2) ranging in size from 1.5 to 4.5 cm. Microscopically, 8 lesions were classified as fibroadenoma, and 5, including 1 recurrent tumor, as phyllodes tumor, of which 1 was benign and 4 low-grade malignant. In addition to conventional findings, we describe several hitherto unreported features including juvenile fibroadenoma-like proliferation, fibroadenoma with lactation change, and pseudoangiomatous stromal hyperplasia with multinucleated stromal giant cells in a patient with neurofibromatosis, type 1 all constituting potential diagnostic pitfalls, which are best averted by using the same approach to diagnosis as for their analogous mammary counterparts.

  16. Mincle Signaling Promotes Con A Hepatitis.

    PubMed

    Greco, Stephanie H; Torres-Hernandez, Alejandro; Kalabin, Aleksandr; Whiteman, Clint; Rokosh, Rae; Ravirala, Sushma; Ochi, Atsuo; Gutierrez, Johana; Salyana, Muhammad Atif; Mani, Vishnu R; Nagaraj, Savitha V; Deutsch, Michael; Seifert, Lena; Daley, Donnele; Barilla, Rocky; Hundeyin, Mautin; Nikifrov, Yuriy; Tejada, Karla; Gelb, Bruce E; Katz, Steven C; Miller, George

    2016-10-01

    Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle(-/-), and Dectin-1(-/-) mice. The role of C/EBPβ and hypoxia-inducible factor-1α (HIF-1α) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ-related signaling intermediates C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPβ and HIF-1α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.

  17. Galaxias australes con núcleo doble

    NASA Astrophysics Data System (ADS)

    Gimeno, G.; Díaz, R.; Carranza, G.

    Se estudia una muestra de galaxias australes con núcleo doble a partir de una búsqueda extensiva en la literatura. Se analizan las características morfológicas, fotométricas y espectroscópicas de la muestra. Para algunas galaxias se han realizado observaciones con el espectrógrafo multifunción (EMF) de la Estación Astrofísica de Bosque Alegre a partir de las cuales se determinaron parámetros cinemáticos.

  18. [Clinical application of three-dimensional O-arm navigation system in treating patients with dystrophic scoliosis secondary to neurofibromatosis type Ⅰ].

    PubMed

    Liu, Z; Qiu, Y; Li, Y; Zhao, Z H; Wang, B; Zhu, F; Yu, Y; Sun, X; Zhu, Z Z

    2017-03-01

    Objective: To investigate the clinical outcomes and the accuracy of O-arm-navigation system assisted pedicle screw insertion in dystrophic scoliosis secondary to neurofibromatosis type Ⅰ(NF-1). Methods: A retrospective study was conducted in 41 patients with dystrophic NF-1-associated thoracic scoliosis who were surgically treated at Department of Orthopaedics, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School between June 2012 and October 2014 with more than 18 months follow-up. The patients were then divided into two groups: 18 patients were under the assistance of O-arm-navigation-based pedicle screw insertion (O-arm group) and the remaining 23 patients' pedicle screws insertion were conducted by free-hand (free-hand group). The X-ray and CT were analyzed to investigate the correction rate and safety of pedicle insertion. t-test was used to analyze measurement data and χ(2) test was used to analyze accuracy of screw insertion between the two groups. Results: The mean coronal Cobb angle was 63.2°±8.7° in the O-arm group and 66.9°±7.4° in the free-hand group (P>0.05), which was then corrected into 23.1°±6.8° and 30.2°±7.6°(t=2.231, P=0.031) after surgery respectively.Operation time was (265.0±70.3)minutes and estimated blood loss was (1 024±465)ml in the O-arm group. Operation time and estimated blood loss was (243.0±49.6)minutes and (1 228±521)ml respectively in the free-hand group, which had no significant difference between the two groups. However, the implant density was higher in the O-arm group than that in the free-hand group ((64.1±10.8)% vs.(44.3±15.3)%)(t=4.652, P=0.000). The O-arm group comprised 122 screws, of which 72.9% were excellent, 22.1% were good and 4.9% were bad. The free-hand group comprised 136 screws and 48.5% of them were excellent, 33.8% were good and 17.6% were bad.Accuracy of pedicle screw insertion was higher in the O-arm group than that in the free-hand group(χ(2)=10.140, P

  19. Gamma Knife radiosurgery for treatment of growing vestibular schwannomas in patients with neurofibromatosis Type 2: a matched cohort study with sporadic vestibular schwannomas.

    PubMed

    Kruyt, Ivo J; Verheul, Jeroen B; Hanssens, Patrick E J; Kunst, Henricus P M

    2017-01-27

    OBJECTIVE Neurofibromatosis Type 2 (NF2) is a tumor syndrome characterized by an autosomal dominant pattern of inheritance. The hallmark of NF2 is the development of bilateral vestibular schwannomas (VSs), generally by 30 years of age. One of the first-line treatment options for small to medium-large VSs is radiosurgery. Although radiosurgery shows excellent results in sporadic VS, its use in NF2-related VS is still a topic of dispute. The aim of this study was to evaluate long-term tumor control, hearing preservation rates, and factors influencing outcome of optimally dosed, contemporary Gamma Knife radiosurgery (GKRS) for growing VSs in patients with NF2 and compare the findings to data obtained in patients with sporadic VS also treated by means of GKRS. METHODS The authors performed a retrospective analysis of 47 growing VSs in 34 NF2 patients who underwent GKRS treatment performed with either the Model C or Perfexion Leksell Gamma Knife, with a median margin dose of 11 Gy. Actuarial tumor control rates were estimated using the Kaplan-Meier method. For patient- and treatment-related factors, a Cox proportional hazards model was used to identify predictors of outcome. Trigeminal, facial, and vestibulocochlear nerve function were assessed before and after treatment. NF2-related VS patients were matched 1:1 with sporadic VS patients who were treated in the same institute, and the same indications for treatment, definitions, and dosimetry were used in order to compare outcomes. RESULTS Actuarial tumor control rates in NF2 patients after 1, 3, 5, and 8 years were 98%, 89%, 87%, and 87%, respectively. Phenotype and tumor volume had significant hazard rates of 0.086 and 22.99, respectively, showing that Feiling-Gardner phenotype and a tumor volume not exceeding 6 cm(3) both were associated with significantly better outcome. Actuarial rates of serviceable hearing preservation after 1, 3, 5, and 7 years were 95%, 82%, 59%, and 33%, respectively. None of the patients

  20. InterCon Travel Health: Case B

    ERIC Educational Resources Information Center

    Truman, Gregory E.; Pachamanova, Dessislava A.; Goldstein, Michael A.

    2010-01-01

    InterCon provides services to health insurers of foreign tourists who travel to the United States and Canada. Management wants to implement a new information system that will deal with several operational problems, but it is having difficulty securing the capital resources to fund the system's development. After an initial failure, the chief…

  1. Neurofibromatosis and the Painful Neuroma

    DTIC Science & Technology

    2010-01-01

    clinical treatment of neuropathic pain and pain from neuroma formation. Systemic administration of lidocaine has also been used to treat neuropathic... pain . We performed an experiment to compare the effect of pregabalin(PGB), morphine, and lidocaine (LDC) on the TNT model. Method: TNT model...of mechanical hyperalgesia (partially dennervated skin). Further, systemic lidocaine can be expected to impact neuroma sensitivity related pain

  2. Neurofibromatosis and the Painful Neuroma

    DTIC Science & Technology

    2008-01-01

    Wheat Germ Agglutinin (WGA) coupled to Saporin as an interesting neuronal toxin. This toxin will bind 5 preferentially to small neuronal fibers...from a neuroma and lead to a significant reduction of neuroma tenderness. Wheat Germ Agglutinin - SAP In our open labeled studies we used doses...application of Wheat Germ Agglutinin – SAP to a nerve will result in retrograde transport of the neural toxin and loss of small fiber axons. In

  3. Neurofibromatosis and the Painful Neuroma

    DTIC Science & Technology

    2009-01-01

    identified two other neural toxins that may be effective: Wheat Germ Agglutinin (WGA) coupled to saporin and cholera toxin B (CTB) coupled to saporin...degeneration. There is a dose dependent loss of axons and prevention of neuroma formation. The application of Wheat Germ Agglutinin – SAP to a nerve will

  4. Preclinical Mouse Models of Neurofibromatosis

    DTIC Science & Technology

    2007-10-01

    in NF1 and NF2 Patients. Persons with NF1 are predisposed to benign neurofibromas, optic nerve gliomas, and to specific malignant neoplasms ...anatomic location. The malignant neoplasms seen in NF1 patients include astrocytoma, malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, and...hematopoietic cells results in a progressive myeloproliferative disorder. Blood 2004; 103: 4243-4250. Reilly KM, Tuskan RG, Christy E, Loisel DA

  5. Preclinical Mouse Models of Neurofibromatosis

    DTIC Science & Technology

    2009-10-01

    benign neurofibromas, optic nerve gliomas, and to specific malignant neoplasms . Individuals with NF1 typically develop multiple neurofibromas that...benign, these tumors frequently cause visual impairment or blindness because of their anatomic location. The malignant neoplasms seen in NF1 patients...muscle layer. All of these properties are indication of malignant neoplasms that are not found in neurofibromas. Abundant melanin pigmentation

  6. Preclinical Mouse Models of Neurofibromatosis

    DTIC Science & Technology

    2006-10-01

    Patients. Persons with NF1 are predisposed to benign neurofibromas, optic nerve gliomas, and to specific malignant neoplasms . Individuals with NF1...malignant neoplasms seen in NF1 patients include astrocytoma, malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, and juvenile...Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci U S A 2004;101(2):597-602. 14. Chan IT, Kutok JL

  7. Preclinical Mouse Models of Neurofibromatosis

    DTIC Science & Technology

    2004-10-01

    plexiform neurofibroma, and chemotherapy- induced leukemia (7-12) and of NF2-associated tumors such as vestibular Schwannoma and meningioma (5, 6). These...to tumors that often require aggressive treatment and because they might be prone to therapy- induced cancers if chemotherapy and radiation induce ...the MPD that results from Nfl inactivation (15), we reasoned that Gab2 might similarly be required to induce leukemia in Nfl mice. The Shannon lab is

  8. Upregulating Apoptotic Signaling in Neurofibromatosis

    DTIC Science & Technology

    2009-09-01

    sNF and ST- 8814 cells were co-immunoprecipitated with a RBD/GST fusion protein and immunoblotting with anti-Ras antibody. Even loading was verified by...led us to test whether hyperactive Ras signaling could be in synergy with loss of PKC in NF deficient condition. Human sNF (MPNST) and ST- 8814 ...can only associate with the active form of Ras (Figs. 2a and b). The association of active Ras with the fusion protein was observed in sNF or ST- 8814

  9. La salud en personas con discapacidad intelectual en España: estudio europeo POMONA-II

    PubMed Central

    Martínez-Leal, Rafael; Salvador-Carulla, Luis; Gutiérrez-Colosía, Mencía Ruiz; Nadal, Margarida; Novell-Alsina, Ramón; Martorell, Almudena; González-Gordón, Rodrigo G.; Mérida-Gutiérrez, M. Reyes; Ángel, Silvia; Milagrosa-Tejonero, Luisa; Rodríguez, Alicia; García-Gutiérrez, Juan C.; Pérez-Vicente, Amado; García-Ibáñez, José; Aguilera-Inés, Francisco

    2011-01-01

    Introducción Estudios internacionales demuestran que existe un patrón diferenciado de salud y una disparidad en la atención sanitaria entre personas con discapacidad intelectual (DI) y población general. Objetivo Obtener datos sobre el estado de salud de las personas con DI y compararlos con datos de población general. Pacientes y métodos Se utilizó el conjunto de indicadores de salud P15 en una muestra de 111 sujetos con DI. Los datos de salud encontrados se compararon según el tipo de residencia de los sujetos y se utilizó la Encuesta Nacional de Salud 2006 para comparar estos datos con los de la población general. Resultados La muestra con DI presentó 25 veces más casos de epilepsia y el doble de obesidad. Un 20% presentó dolor bucal, y existió una alta presencia de problemas sensoriales, de movilidad y psicosis. Sin embargo, encontramos una baja presencia de patologías como la diabetes, la hipertensión, la osteoartritis y la osteoporosis. También presentaron una menor participación en programas de prevención y promoción de la salud, un mayor número de ingresos hospitalarios y un uso menor de los servicios de urgencia. Conclusiones El patrón de salud de las personas con DI difiere del de la población general, y éstas realizan un uso distinto de los servicios sanitarios. Es importante el desarrollo de programas de promoción de salud y de formación profesional específicamente diseñados para la atención de personas con DI, así como la implementación de encuestas de salud que incluyan datos sobre esta población. PMID:21948011

  10. [A novel neurocutaneous syndrome: Legius syndrome. A case report].

    PubMed

    Cemeli-Cano, Mercedes; Peña-Segura, José Luis; Fernando-Martínez, Ruth; Izquierdo-Álvarez, Silvia; Monge-Galindo, Lorena; López-Pisón, Javier

    2014-09-01

    Introduccion. El sindrome de Legius es un trastorno autosomico dominante resultante de la mutacion del gen SPRED1, que implica perdida de funcion de una de las proteinas implicada en la via patogenica RAS-MAPK, similar a la neurofibromina y por ello muestra similitudes clinicas con la neurofibromatosis tipo 1 (NF1), pero con menor gravedad. Estos pacientes presentan multiples manchas cafe con leche y pueden asociar efelides, rasgos dismorficos, lipomas y trastornos del aprendizaje sin relacionarse con la aparicion de neurofibromas, gliomas opticos, nodulos de Lisch o predisposicion tumoral. Caso clinico. Niño de 10 meses, sin antecedentes personales de interes, que consulta por hipotonia de extremidades, manchas cafe con leche y leve retraso psicomotor. En los antecedentes familiares destaca una hermana de la madre y el abuelo materno con manchas cafe con leche. En nuestro paciente, el estudio genetico fue negativo para NF1, pero se hallo una mutacion en el gen SPRED1, compatible con el sindrome de Legius. La madre asintomatica presenta la misma mutacion en el gen SPRED1. Conclusion. Es de destacar la importancia del diagnostico diferencial de NF1, con las numerosas complicaciones que puede conllevar, con una entidad recientemente descrita de mejor pronostico como es el sindrome de Legius.

  11. Somatic cell nuclear transfer: pros and cons.

    PubMed

    Sumer, Huseyin; Liu, Jun; Tat, Pollyanna; Heffernan, Corey; Jones, Karen L; Verma, Paul J

    2009-01-01

    Even though the technique of mammalian SCNT is just over a decade old it has already resulted in numerous significant advances. Despite the recent advances in the reprogramming field, SCNT remains the bench-mark for the generation of both genetically unmodified autologous pluripotent stem cells for transplantation and for the production of cloned animals. In this review we will discuss the pros and cons of SCNT, drawing comparisons with other reprogramming methods.

  12. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  13. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  14. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  15. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  16. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  17. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  18. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  19. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  20. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  1. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  2. Finemet versus ferrite -- Pros and cons

    SciTech Connect

    K.Y. Ng and Z.B. Qian

    1999-05-19

    There is a new magnetic alloy called Finemet which has very constant {mu}'{sub p}Qf up to {approximately} 2 kG and is very stable at high magnet flux density and temperature. It may be a good can-didate for high-gradient rf cavities. However, it has a rather low quality factor and is therefore very lossy. We compare the pros and cons of Finemet versus the common ferrite, when used in low-energy accelerating cavities, insertion for space-charge compensation, and barrier cavities.

  3. Giant thrombosed intracavernous carotid artery aneurysm presenting as Tolosa–Hunt syndrome in a patient harboring a new pathogenic neurofibromatosis type 1 mutation: a case report and review of the literature

    PubMed Central

    Conforti, Renata; Cirillo, Mario; Marrone, Valeria; Galasso, Rosario; Capaldo, Guglielmo; Giugliano, Teresa; Scuotto, Assunta; Piluso, Giulio; Melone, Mariarosa AB

    2014-01-01

    Neurofibromatosis type 1 (NF1) is a relatively common single-gene disorder, and is caused by heterozygous mutations in the NF1 gene that result in a loss of activity or in a nonfunctional neurofibromin protein. Despite the common association of NF1 with neurocutaneous features, its pathology can extend to numerous tissues not derived from the neural crest. Among the rare cerebrovascular abnormalities in NF1, more than 85% of cases are of purely occlusive or stenotic nature, with intracranial aneurysm being uncommon. Predominantly, the aneurysms are located in the internal carotid arteries (ICAs), being very rare bilateral aneurysms. This report describes a very unusual case of fusiform aneurysms of both ICAs in a Caucasian NF1 patient, with a new pathogenic intragenic heterozygous deletion of the NF1 gene, presenting at age 22 years with Tolosa–Hunt syndrome, because of partial thrombosis of the left giant intracavernous aneurysm. Medical treatment with anticoagulant therapy allowed a good outcome for the patient. In conclusion, early identification of cerebral arteriopathy in NF1 and close follow-up of its progression by neuroimaging may lead to early medical or surgical intervention and prevention of significant neurologic complications. PMID:24476631

  4. An Update on Neurofibromatosis Type 1: Not Just Café-au-Lait Spots and Freckling. Part II. Other Skin Manifestations Characteristic of NF1. NF1 and Cancer.

    PubMed

    Hernández-Martín, A; Duat-Rodríguez, A

    2016-01-01

    Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still based primarily on clinical observations. The 7 diagnostic criteria of the National Institutes of Health, which were established in 1988, include 3 skin manifestations (café-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas). The age at which these diagnostic lesions appear is variable: onset can be late in some patients while others never develop certain symptoms. Definitive diagnosis may therefore be delayed by years. Although the appearance of the characteristic café-au-lait spots and freckling in the early years of childhood are very suggestive of the disease, these signs are not pathognomonic and, in isolation, do not constitute sufficient evidence to establish a definitive diagnosis. Thus, other diagnoses should be considered in patients whose only symptoms are café-au-lait spots and freckling. By contrast, the presence of multiple cutaneous neurofibromas or at least 1 plexiform neurofibroma is a very specific indication of NF1. Identification of the different types of neurofibroma allows us to confirm the diagnosis and initiate appropriate management.

  5. A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

    PubMed

    Tong, H-X; Li, M; Zhang, Y; Zhu, J; Lu, W-Q

    2012-08-29

    Neurofibromatosis type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1 gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. In this study, we present a clinical and molecular study of a Chinese patient with giant café-au-lait in NF1. The patient showed >6 café-au-lait spots on the body, axillary freckling, and multiple subcutaneous neurofibromas. He also had a malignant peripheral nerve sheath tumor and bone abnormalities. The germline mutational analysis of the NF1 gene revealed a novel missense mutation in exon 13. It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath tumor DNA from this patient. This expands the database for NF1 gene mutations in NF1. Its absence in the normal chromosomes suggests that it is responsible for the NF1 phenotype. To our knowledge, this is the first case of giant café-au-lait macule in NF1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

  6. 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.

    PubMed

    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.

  7. The Key Search Subtest of the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C) Instrument Reveals Impaired Planning Without External Constraints in Children With Neurofibromatosis Type 1.

    PubMed

    Riva, Daria; Vago, Chiara; Erbetta, Alessandra; Saletti, Veronica; Esposito, Silvia; Micheli, Roberto; Bulgheroni, Sara

    2017-03-01

    Studies of executive function and its relationship with brain T2-weighted hyperintensities in children with neurofibromatosis type 1 (NF1) have yielded inconsistent results. We examined 16 children with NF1 aged 8 to 15 years, of normal intelligence, and compared their findings to those of 16 siblings and 16 typically developing children using the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C). NF1 patients had an adequate overall score at BADS-C, but showed significantly lower performance than typical peers in the Key Search subtest. This is a task that must be solved without any given rules, in which subjects must devise a strategy and an efficient search pattern transferable to other similar real situations. The Key Search scores were not correlated with number and signal characteristics of T2-weighted hyperintensities. Planning without external indications is impaired in children with NF1 because they have to rely entirely on self-organization and monitoring; this study provides information for remediation programs designed to improve functioning in daily life.

  8. TATA-Binding Protein (TBP)-Like Factor (TLF) Is a Functional Regulator of Transcription: Reciprocal Regulation of the Neurofibromatosis Type 1 and c-fos Genes by TLF/TRF2 and TBP

    PubMed Central

    Chong, Jayhong A.; Moran, Magdalene M.; Teichmann, Martin; Kaczmarek, J. Stefan; Roeder, Robert; Clapham, David E.

    2005-01-01

    The lack of direct targets for TATA-binding protein (TBP)-like factors (TLFs) confounds the understanding of their role in gene expression. Here we report that human TLF (also called TBP-related factor 2 [TRF2]) activates a number of different genes, including the neurofibromatosis type 1 (NF1) gene. The overexpression of TLF increases the amount of NF1 mRNA in cells. In vivo, TLF binds to and upregulates transcription from a fragment of the NF1 promoter. In vitro, purified TLF-TFIIA binds directly to the same NF1 promoter fragment that is required for TLF responsiveness in cells. Furthermore, targeted deletion of TLF in mice reduces NF1 levels. In contrast, TLF inhibits transcription driven by a fragment from the TATA-containing c-fos promoter by sequestering TFIIA. TBP affects the NF1 and c-fos promoters in a manner reciprocal to that of TLF, stimulating the c-fos promoter and inhibiting NF1 transcription. We conclude that TLF is a functional regulator of transcription with targets distinct from those of TBP. PMID:15767669

  9. Energy Star program benefits Con Edison

    SciTech Connect

    1995-05-01

    Impressed with savings in energy costs achieved after upgrading the lighting and air conditioning systems at its Manhattan headquarters, Home Box Office (HBO) wanted to do more, James Flock, vice president for computer and office systems, contacted Con Edison Co. of New York in March 1991 to determine what the company could do to save money by reducing energy consumed by personal computers. Arthur Kressner, Con Edison Research and Development manager contacted industry organizations and manufacturers for advice, but was told only to shut off computers at night and on weekends. Kressner arranged a series of meetings with IBM and the Electric Power Research Institute (EPRI) to discuss the issue, then approached the U.S. Environmental Protection Agency (EPA), which was designing a program to promote the introduction and use of energy-efficient office equipment. In 1992, the EPA announced the Energy Star program for PCs, enabling manufacturers to display the Energy Star logo on machines meeting program criteria, including the ability to enter a sleep mode in which neither the computer nor monitor consume more than 30 W or electricity. Industry experts estimate national energy consumption by office equipment could double by the year 2000, but Energy Star equipment is expected to improve efficiency and help maintain electric loads.

  10. Actitudes Éticas de los estudiantes y egresados en carrera de medicina con metodologías activas

    PubMed Central

    Novaes, Maria Rita Carvalho Garbi; Novaes, Luiz Carlos Garcez; Guilhem, Dirce; Stepke, Fernando Lolas; Silveira, Carla Cristina Costa; Komatsu, Ricardo Shoiti; Trindade, Eliane Mendonça Vilar; Guiotti, Murilo Galvão

    2010-01-01

    El presente estudio tiene por objeto desarrollar un diagnostico de la inserción integrada de la ética en la carrera de medicina brasileña con una metodología de aprendizaje basada en problemas y describir las percepciones de actitudes éticas de los estudiantes y egresados. El diseño metodológico es un estudio de caso, descriptivo y documental, con abordaje cualitativo y cuantitativo. La muestra de esta investigación ha sido constituida por 120 estudiantes y 40 egresados de dos promociones del Curso de Medicina de la ESCS. Este proyecto fue aprobado por el Comité de Ética en Investigación - SES/DF. Los estudiantes y egresados de la ESCS demostraron un buen manejo en el abordaje de los conflictos éticos y respeto a los pacientes. Sin embargo, el análisis de sensibilidad ética mostró una fragilidad en las percepciones y aptitudes inapropiadas de los estudiantes de la carrera de medicina, identificada básicamente en los años iniciales, que necesitan más discusiones sistematizadas sobre los aspectos éticos y bioéticos integrados a las actividades prácticas para estimular y fortalecer la reflexión ética de los estudiantes. PMID:20981242

  11. Cervical disc arthroplasty: Pros and cons

    PubMed Central

    Moatz, Bradley; Tortolani, P. Justin

    2012-01-01

    Background: Cervical disc arthroplasty has emerged as a promising potential alternative to anterior cervical discectomy and fusion (ACDF) in appropriately selected patients. Despite a history of excellent outcomes after ACDF, the question as to whether a fusion leads to adjacent segment degeneration remains unanswered. Numerous US investigational device exemption trials comparing cervical arthroplasty to fusion have been conducted to answer this question. Methods: This study reviews the current research regarding cervical athroplasty, and emphasizes both the pros and cons of arthroplasty as compared with ACDF. Results: Early clinical outcomes show that cervical arthroplasty is as effective as the standard ACDF. However, this new technology is also associated with an expanding list of novel complications. Conclusion: Although there is no definitive evidence that cervical disc replacement reduces the incidence of adjacent segment degeneration, it does show other advantages; for example, faster return to work, and reduced need for postoperative bracing. PMID:22905327

  12. Pros and cons of the proteomics.

    PubMed

    Gupta, Ashish; Kumar, Ashutosh

    2014-01-01

    The number of proteins produced by the 30,000-40,000 genes of the human genome is estimated to be three or four orders of magnitude higher. Proteomics is a rapidly developing science. In principle, two main areas in the field of proteomics have been developed, each of them having its pros and cons. These fields are profiling and functional proteomics. The aim of the proteomic profiling is to describe and index the whole set of proteins of a biological sample, which could be an organism, an organ, or a cell, or parts there of like individual's tissue or organelles. In our understanding, both types of proteomics (profiling and functional) are valuable tools complementing other biological methodologies.

  13. Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1*♦

    PubMed Central

    Hirata, Yasuko; Brems, Hilde; Suzuki, Mayu; Kanamori, Mitsuhiro; Okada, Masahiro; Morita, Rimpei; Llano-Rivas, Isabel; Ose, Toyoyuki; Messiaen, Ludwine; Legius, Eric; Yoshimura, Akihiko

    2016-01-01

    Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120GAP. Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome. PMID:26635368

  14. Pros and cons of phage therapy

    PubMed Central

    Loc-Carrillo, Catherine

    2011-01-01

    Many publications list advantages and disadvantages associated with phage therapy, which is the use of bacterial viruses to combat populations of nuisance or pathogenic bacteria. The goal of this commentary is to discuss many of those issues in a single location. In terms of “Pros,” for example, phages can be bactericidal, can increase in number over the course of treatment, tend to only minimally disrupt normal flora, are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria, often are easily discovered, seem to be capable of disrupting bacterial biofilms, and can have low inherent toxicities. In addition to these assets, we consider aspects of phage therapy that can contribute to its safety, economics, or convenience, but in ways that are perhaps less essential to the phage potential to combat bacteria. For example, autonomous phage transfer between animals during veterinary application could provide convenience or economic advantages by decreasing the need for repeated phage application, but is not necessarily crucial to therapeutic success. We also consider possible disadvantages to phage use as antibacterial agents. These “Cons,” however, tend to be relatively minor. PMID:22334867

  15. Pro/con a precessional geodynamo

    NASA Astrophysics Data System (ADS)

    Vanyo, J.

    2003-04-01

    The modest amount of research that exists on the ability, or lack of ability, of mantle precession to power a geodynamo developed mostly during the last half of the 1900s. Papers by Roberts and Stewartson (1965) and by Busse (1968) studied precession generally without a pro/con conclusion. Malkus in the late 1960s attempted to advance a positive role for precession through experiments and analysis. His experiments have survived criticism, but his analyses were discounted, especially by Rochester, Jacobs, Smylie, and Chong (1975) and by Loper (1975). Rochester, et al. critiqued existing analyses of precession, including those of Malkus, but did not reach a strong position either pro or con a precessional geodynamo. Loper argued emphatically that precession was not capable of powering the geodynamo. Explicit analyses that either critique or support Loper’s arguments have yet to appear in the literature. During the 1970s, Vanyo and associates studied energy dissipation during precession of satellite liquid fuels and its effect on satellite attitude stability. Engineers and scientists in every country that has launched satellites completed similar research. Some is published in the aerospace literature, more is available in company and government reports. Beginning in 1981, Vanyo and associates applied this knowledge to the very similar problem of energy dissipation and flow patterns in precessing mechanical models scaled geometrically and dynamically to the Earth’s liquid core. Energy experiments indicate massive amounts of mechanical energy are dissipated at the CMB, and flow experiments show complex motions within the boundary layer and axial flows with helicity throughout the interior. Analysis of Earth core precession also advanced, especially in several papers by Kerswell and by Tilgner in the late 1990s. Detail numerical models have yet to appear. Although progress in understanding the role of precession in Earth core motions has advanced, there remains a

  16. Trazando la materia oscura con cúmulos globulares

    NASA Astrophysics Data System (ADS)

    Forte, J. C.

    Se describe la estrategia adoptada para mapear la distribución de materia oscura y bariónica en galaxias elípticas cuyos cúmulos globulares están siendo observados con los telescopios VLT y Gemini. Se ejemplifican los resultados con los datos obtenidos en el cúmulo de Fornax.

  17. Games Con Men Play: The Semiosis of Deceptive Interaction.

    ERIC Educational Resources Information Center

    Hankiss, Agnes

    1980-01-01

    Analyzes some of the most frequent deceptive interactions as rendered through case histories of male con artists and their victims taken from police records. Discusses the recurrent elements in both the con-games strategies and victims' way of interpreting those strategies. (JMF)

  18. Breath Analysis Science at PittCon 2012, Orlando, Florida

    EPA Science Inventory

    Breath analysis science was featured in three organized sessions at this year’s Pittsburgh Conference and Exposition, or ‘PittCon 2012’ (http://www.pittcon.org/). As described in previous meeting reports, PittCon is one of the largest international conferences for analytical chem...

  19. RoboCon: A general purpose telerobotic control center

    SciTech Connect

    Draper, J.V.; Noakes, M.W.; Schempf, H.; Blair, L.M.

    1997-02-01

    This report describes human factors issues involved in the design of RoboCon, a multi-purpose control center for use in US Department of Energy remote handling applications. RoboCon is intended to be a flexible, modular control center capable of supporting a wide variety of robotic devices.

  20. [Cement augmentation of pedicle screws : Pros and cons].

    PubMed

    Schnake, K J; Blattert, T R; Liljenqvist, U

    2016-09-01

    Cement augmentation of pedicle screws biomechanically increases screw purchase in the bone. However, clinical complications may occur. The pros and cons of the technique are discussed from different clinical perspectives.

  1. [I costi farmacologici della terapia di conversione con farmaci biologici nel carcinoma del colon-retto con metastasi epatiche].

    PubMed

    Giuliani, Jacopo; Bonetti, Andrea

    2016-08-01

    Riassunto. Lo scopo di questo studio è quello di valutare i costi dei farmaci (con particolare riferimento alle terapie con farmaci biologici) utilizzati nella terapia di conversione in una popolazione non selezionata di pazienti affetti da carcinoma del colon-retto in stadio avanzato, al fine di ottenere una resezione epatica R0. In questa rassegna sono stati selezionati i report completi e gli aggiornamenti di tutti gli studi clinici randomizzati (di fase II e fase III) che confrontassero almeno 2 regimi di terapia con farmaci biologici in prima linea in pazienti affetti da carcinoma del colon-retto in stadio avanzato di malattia. I costi dei farmaci sono stati ricavati dalla nostra Farmacia Ospedaliera e sono espressi in euro (€). Il nostro studio inizia con la valutazione di 683 abstract. 48 tria sono stati considerati adeguati per una successiva analisi. Una valutazione più approfondita ha portato all'esclusione di 37 trial, lasciando alla valutazione finale 11 studi clinici randomizzati (3 trial di fase II, per un totale di 522 pazienti, e 8 studi di fase III, per un totale di 7191 pazienti). I costi dei farmaci utilizzati nella terapia di conversione aumentano con la sostituzione del 5-fluorouracile con la capecitabina e, in misura maggiore, con l'introduzione degli agenti biologici. In questo lavoro sono presentati due punti chiave. Primo, i costi degli agenti farmacologici utilizzati nei regimi di prima linea a base di agenti biologici più comunemente utilizzati nel trattamento del carcinoma del colon-retto in stadio avanzato sono molto variabili. Secondo, i dati di efficacia dei regimi pubblicati, in termini di tassi di resezione, dipendono dalla selezione dei pazienti, dalle caratteristiche del tumore e dal tipo di schema di terapia.

  2. Detail of conning tower atop the submarine. Note the wire ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Detail of conning tower atop the submarine. Note the wire rope wrapped around the base of the tower, which may have been used in an attempt to pull the submarine offshore. - Sub Marine Explorer, Located along the beach of Isla San Telmo, Pearl Islands, Isla San Telmo, Former Panama Canal Zone, CZ

  3. Utilice en forma segura los productos con cebo para roedores

    EPA Pesticide Factsheets

    Si se usan de manera inadecuada, los productos con veneno para ratas y ratones podrían hacerle daño a usted, a sus hijos o a sus mascotas. Siempre que use pesticidas lea la etiqueta del producto y siga todas las indicaciones.

  4. Canceling Some d-CON Mouse and Rat Control Products

    EPA Pesticide Factsheets

    EPA has reached agreement with the manufacturer, to cancel 12 d-CON products that do not meet our testing protocols that better protect children, pets and non-target wildlife from accidental exposure to the pesticide. These products will be phased out.

  5. Three dimensional boundary layers on submarine conning towers and rudders

    NASA Astrophysics Data System (ADS)

    Gleyzes, C.

    1988-01-01

    Solutions for the definition of grids adapted to the calculation of three-dimensional boundary layers on submarine conning towers and on submarine rudders and fins are described. The particular geometry of such bodies (oblique shaped hull, curved fins) required special adaptations. The grids were verified on examples from a test basin.

  6. Providers debate pros and cons of pneumonia vaccination at discharge.

    PubMed

    2001-02-01

    When to vaccinate against pneumonia? Does it makes sense when patients are in the hospital? Or should patients wait for the first post-op visit with the PCP? Office-based and hospital-based physicians weigh the pros and cons of each.

  7. International Field Reversible Thermal Connector (RevCon) Challenge

    DTIC Science & Technology

    2016-07-01

    of Figures Figure Page Figure 1: Comparison Temperature History of T3 from each Thermal Connector........................ 6...OHP Thermal Connector Delivered by MissStateU .................................................. 54 Figure 49: Comparison Temperature History of T1...88 Figure A2: Schematic of Temperature Monitoring and Vibration Detection Setup for RevCon IV

  8. Teaching after Retirement: The Pros and the Cons

    ERIC Educational Resources Information Center

    Sommer, Robert

    2014-01-01

    Having enjoyed teaching during my active career, I continued to teach summer school following retirement. Self-observed sensory and cognitive impairments, although not mentioned by students in their evaluations, induced me to consider the pros and cons of continuing to teach. My hope is that this list of benefits and problems will be of assistance…

  9. Inclusion: The Pros and Cons--A Critical Review

    ERIC Educational Resources Information Center

    Savich, Carl

    2008-01-01

    The purpose of this paper was to review, analyze, and critique the pros and cons, the advantages and disadvantages, of inclusion. The methodology consisted in analyzing and comparing research findings on the benefits and costs of inclusion. Federal legislation and regulations on inclusion were examined, analyzed, and discussed. The results showed…

  10. Relación Entre el Tamaño Condilar y la Asimetría Facial Transversal en Individuos con Hiperplasia Condilar

    PubMed Central

    Olate, Sergio; Cantín, Mario; Alister, Juan Pablo; Uribe, Francisca; Navarro, Pablo; Olate, Gabriela; de Moraes, Márcio

    2016-01-01

    La asimetría facial es una patología de compromiso funcional y estético que puede estar generado por hiperplasia condilar; el objetivo de esta investigación es determinar la influencia del tamaño condilar en la asimetría facial. Doce sujetos fueron estudiados mediante el análisis de tomografía computadorizada cone beam; todos los pacientes presentaron cintigrama óseo que determino la presencia de hiperplasia condilar activa; el análisis se realizo en un software del sistema de captura modelo Pax Zenith, marca Vatech (Korea 2011), utilizando 90 kV y 120 mA; se obtuvo mediciones de la distancia antero-posterior, superior-inferior y medio-lateral de la cabeza del cóndilo, relacionándose con la posición del cóndilo con la línea mediana facial y la posición de puntos faciales entre incisivos centrales superior e inferior así como con el mentón. Los resultados mostraron un promedio de desvío de mentón de 6,5 mm considerando un cóndilo hiperplásico con un tamaño de 2,7 mm mas que los cóndilos normales. El desvío de incisivo central inferior determinó que por cada 1 mm de desvío dentario existe 2,2 mm de desvío de mentón. El cóndilo hiperplásico fue de mayor tamaño y se posiciono casi 2 mm mas hacia lateral que los cóndilos no hiperplásicos. Es posible concluir que el cóndilo hiperplásico presenta clara influencia en la asimetría facial transversa y es posible estimar una relación de tamaño condilar con grado de asimetría facial. PMID:28066127

  11. LunGradCon: The Lunar Graduate Conference

    NASA Astrophysics Data System (ADS)

    Dove, A.; Poppe, A.; Neish, C.; Fagan, A.; Fuqua, H.; Kramer, G. Y.; Horanyi, M.

    2011-12-01

    Members of the Colorado Center for Lunar Dust and Atmospheric Studies (CCLDAS) initiated the Lunar Graduate Conference (LunGradCon), modeled after the highly successful Astrobiology Graduate Conference (AbGradCon). The purpose of this conference is to enhance the professional development of graduate students and early postdoctoral researchers by providing an opportunity to present and discuss scientific research in an environment of their peers. For the first two years, LunGradCon has been held as a one-day conference in conjunction with the NASA Lunar Science Institue's (NLSI) Lunar Science Forum at the NASA Ames Research Center. Activities include an invited overview talk on each of the NASA Lunar Science Institute's three main research areas (OF the Moon, ON the Moon, and FROM the Moon), submitted oral presentations from graduate students and postdoctoral researchers, and networking opportunities with established member of the lunar science community and the NLSI. In each of the first two years of LunGradCon, there have been 20-25 attendees, with about 15 of those presenting submitted talks. Each speaker received feedback forms from the other participants in order to improve on their presentation techniques. Participants also provided feedback on the conference as a whole in order to evaluate the content and provide suggestions for improvement in following years. Overall, the feedback has been extremely positive. This talk will summarize the achievements of past LunGradCons and plans for expansion of the conference to ensure a long-term positive impact on the early careers of future lunar, planetary and space science researchers.

  12. Facing Neurofibromatosis: A Guide for Teens

    MedlinePlus

    ... doctor. Neurofibromas can be removed surgically or with laser therapy. However, it’s important to remember that these ... with NF1, to monitor their blood pressure, because high blood pressure (hypertension) can cause a weakening of ...

  13. CT appearance of thickened nerves in neurofibromatosis

    SciTech Connect

    Daneman, A.; Mancer, K.; Sonley, M.

    1983-11-01

    In neutrofibromatosis (von Recklinghausen disease), peripheral nerves may develop enlarged diameters or focal fusiform enlargement due to neurofibromatous involvement. Their appearance on computed tomography (CT) forms the basis of this report.

  14. Images in clinical medicine: Segmental neurofibromatosis.

    PubMed

    Ma, Dong-Lai; Hu, Jin

    2015-03-05

    A 4-year-old girl presented for evaluation of cutaneous nodules that had been present on the left side of her trunk since birth. Physical examination revealed numerous soft, nontender papules and nodules across the left upper abdomen and wrapping around to the back.

  15. Genotype Phenotype Relationships in Neurofibromatosis 2

    DTIC Science & Technology

    2001-10-01

    expression or lack of expression of mutated NF2 alleles. Of the 23 unfound samples tested , 3 (13%) produced an alteration in one or more of the 6 cDNA...mutation in exon 15 of unclear significance. Loss of heterozygosity of flanking and intra genic markers was seen in 19 of the 26 tumors when compared...to blood specimens. When multiple markers were tested across the NF2 region, all but one tumor showed loss at all informative markers or retention at

  16. Genotype Phenotype Relationships in Neurofibromatosis 2

    DTIC Science & Technology

    2000-10-01

    described below showing under expression or lack of expression of mutated NF2 alleles. Of the 23 unfound samples tested , 3 (13%) produced an alteration in...carried a previously undescribed missense mutation in exon 15 of unclear significance. Loss of heterozygosity of flanking and intra genic markers was...seen in 19 of the 26 tumors when compared to blood specimens. When multiple markers were tested across the NF2 region, all but one tumor showed loss at

  17. Posttranscriptional Regulation of the Neurofibromatosis 2 Gene

    DTIC Science & Technology

    2006-07-01

    0.1% Tween) three times, placed in 100% methanol, and then bleached at room temperature for 5 hr by adding hydrogen peroxide to 6%. After rinsing with...Mukhopadhyay A, Banerjee S, Stafford LJ, et al. Curcumin - induced suppression of cell proliferation correlates with down-regulation of cyclin D1 expression

  18. The University of Chicago Neurofibromatosis Program

    DTIC Science & Technology

    2006-11-01

    development treatment protocols for learning disabilities in children with NF1. As part of this process, Dr. Giola and I attended a consensus conference...in Los Angeles with international leaders in the field of NF1 and learning disabilities and discussed potential treatments for learning problems as...for the assessment of learning disabilities and their treatment using Lovastatin. The choice of Lovastatin was based on experimental studies in the

  19. Vestibular Schwannoma (Acoustic Neuroma) and Neurofibromatosis

    MedlinePlus

    ... MD 20892-3456 Toll-free voice: (800) 241-1044 Toll-free TTY: (800) 241-1055 Email: nidcdinfo@ ... questions in English or Spanish. Voice: (800) 241-1044 TTY: (800) 241-1055 nidcdinfo@nidcd.nih.gov ...

  20. A complex photoreceptor system mediates the regulation by light of the conidiation genes con-10 and con-6 in Neurospora crassa.

    PubMed

    Olmedo, María; Ruger-Herreros, Carmen; Luque, Eva M; Corrochano, Luis M

    2010-04-01

    Genes con-10 and con-6 in Neurospora crassa are activated during conidiation or after illumination of vegetative mycelia. Light activation requires the white-collar complex (WCC), a transcription factor complex composed of the photoreceptor WC-1 and its partner WC-2. We have characterized the photoactivation of con-10 and con-6, and we have identified 300bp required for photoactivation in the con-10 promoter. A complex stimulus-response relationship for con-10 and con-6 photoactivation suggested the activity of a complex photoreceptor system. The WCC is the key element for con-10 activation by light, but we suggest that other photoreceptors, the cryptochrome CRY-1, the rhodopsin NOP-1, and the phytochrome PHY-2, modify the activity of the WCC for con-10 photoactivation, presumably through a repressor. In addition we show that the regulatory protein VE-1 is required for full photocarotenogenesis. We propose that these proteins may modulate the WCC in a gene-specific way.