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.

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.

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…

Gene Therapy for Childhood Neurofibromatosis

DTIC Science & Technology

2014-05-01

Neurofibromatosis PRINCIPAL INVESTIGATOR: Segal, David J. CONTRACTING ORGANIZATION: University of California, Davis Davis, California...May 2014 4. TITLE AND SUBTITLE Gene Therapy for Childhood Neurofibromatosis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-13-1-0101 5c...project was to develop an innovative therapy for neurofibromatosis . Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders (1

Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases.

PubMed

Wolkenstein, P; Zeller, J; Revuz, J; Ecosse, E; Leplège, A

2001-11-01

Neurofibromatosis type 1 affects quality of life (QoL) through association with severe complications, impact on cosmetic features, and uncertainty of the effects of the disorder. To evaluate the impact of the severity and visibility of neurofibromatosis type 1 on QoL. Monocenter, cross-sectional study. One French academic dermatological and neurofibromatoses clinic. A total of 128 adult patients with neurofibromatosis type 1. Evaluation of severity and visibility using, respectively, the Riccardi and Ablon scales. Evaluation of skin disease-specific and general QoL using, respectively, Skindex-France and SF-36 (Short Form 36 health survey) profiles controlled for sex, age, severity, and visibility. In a multiple regression model controlling for sex, age, and visibility, visibility remained independently associated with the alteration of 3 aspects of the skin disease-specific QoL (Skindex-France): emotions, physical symptoms, and functioning (P =.03, P =.009, and P =.002, respectively). Patients with more severe neurofibromatosis reported more effects on the following domains of their general health QoL (SF-36): physical function, bodily pain, general health perception, and vitality (P =.006, P =.03, P =.01, and P =.04, respectively). Neurofibromatosis type 1 has a significant impact on QoL through alteration of health and appearance. The consequences of visibility and severity from the viewpoint of patients can be evaluated using Skindex and the SF-36, respectively.

Mosaic generalized neurofibromatosis 1: report of two cases.

PubMed

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

2014-01-01

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

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

DTIC Science & Technology

2011-08-01

AWARD NUMBER: W81XWH-10-1-0469 TITLE: Genetic Evaluation for the Scoliosis Gene(s) in...Patients with Neurofibromatosis Type I and Scoliosis PRINCIPAL INVESTIGATOR: David W. Polly, Jr., M.D. CONTRACTING ORGANIZATION: University...for the Scoliosis Gene(s) in Patients with Neurofibromatosis Type I and Scoliosis 5b. GRANT NUMBER W81XWH-10-1-0469 5c. PROGRAM ELEMENT NUMBER 6

A novel approach in managing right-sided haemothorax in neurofibromatosis type 1.

PubMed

Mydin, Muhammad Izanee Mohamed; Sharma, Amit; Zia, Zergham; Hawari, Mohammad; Jadoon, Mehmood; Majewski, Andrzej

2015-06-01

Spontaneous haemothorax due to vasculopathy in patients with neurofibromatosis type 1 is rare but life-threatening. A 56-year-old lady with neurofibromatosis type 1 presented with right-sided chest pain, dyspnoea, and collapse. Computed tomography showed a right-sided hemothorax. Urgent angiography showed contrast leakage from a right subclavian artery pseudoaneurysm. A Gore Viabahn endovascular stent graft was deployed. Completion angiography revealed satisfactory haemostasis. She underwent video-assisted thoracoscopic evacuation of the hemothorax, with good results. This case highlights a novel approach to managing a rare emergency, using combined procedures. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Numerical Activities of Daily Living in Adults with Neurofibromatosis Type 1

ERIC Educational Resources Information Center

Burgio, F.; Benavides-Varela, S.; Arcara, G.; Trevisson, E.; Frizziero, D.; Clementi, M.; Semenza, C.

2017-01-01

Background: This study aimed to identify the mathematical domains affected in adults with neurofibromatosis 1 (NF1) and the impact of the numerical difficulties on the patients' activities of daily living. Methods: We assessed 28 adult patients with NF1 and 28 healthy control participants. All participants completed the standardised battery of…

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.

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…

Multiple gastrointestinal stromal tumors in type I neurofibromatosis: a pathologic and molecular study.

PubMed

Yantiss, Rhonda K; Rosenberg, Andrew E; Sarran, Lisa; Besmer, Peter; Antonescu, Cristina R

2005-04-01

Multiple gastrointestinal stromal tumors typically occur in familial form associated with KIT receptor tyrosine kinase or platelet-derived growth factor receptor-alpha (PDGFRA) germline mutations, but may also develop in the setting of type 1 neurofibromatosis. The molecular abnormalities of gastrointestinal stromal tumors arising in neurofibromatosis have not been extensively studied. We identified three patients with type 1 neuro-fibromatosis and multiple small intestinal stromal tumors. Immunostains for CD117, CD34, desmin, actins, S-100 protein, and keratins were performed on all of the tumors. DNA was extracted from representative paraffin blocks from separate tumor nodules in each case and subjected to a nested polymerase chain reaction, using primers for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18, followed by direct sequencing. The mean patient age was 56 years (range: 37-86 years, male/female ratio: 2/1). One patient had three tumors, one had five, and one had greater than 10 tumor nodules, all of which demonstrated histologic features characteristic of gastrointestinal stromal tumors and stained strongly for CD117 and CD34. One patient died of disease at 35 months, one was disease free at 12 months and one was lost to follow-up. DNA extracts from 10 gastrointestinal stromal tumors (three from each of two patients and four from one patient) were subjected to polymerase chain reactions and assessed for mutations. All of the tumors were wild type for KIT exons 9, 13, and 17 and PDGFRA exons 12 and 18. Three tumors from one patient had identical point mutations in KIT exon 11, whereas the other tumors were wild type at this locus. We conclude that, although most patients with type 1 neurofibromatosis and gastrointestinal stromal tumors do not have KIT or PDGFRA mutations, KIT germline mutations might be implicated in the pathogenesis of gastrointestinal stromal tumors in some patients.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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.

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

Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin Pathway in Fracture Repair and Pseudarthrosis PRINCIPAL INVESTIGATOR...Award Number: W81XWH-13-1-0113 TITLE: Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta-Catenin...31 May 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Discovery of Novel Drugs To Improve Bone Health in Neurofibromatosis Type 1: The Wnt/Beta

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,…

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.…

Coexistence of Ankylosing Spondylitis and Neurofibromatosis Type 1.

PubMed

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

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.

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…

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...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Patients with Neurofibromatosis (NF1

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.

Neurofibromatosis (For Parents)

MedlinePlus

... Staying Safe Videos for Educators Search English Español Neurofibromatosis KidsHealth / For Parents / Neurofibromatosis What's in this article? ... Diagnosis Treatment Caring for Your Child Print About Neurofibromatosis Neurofibromatosis (NF) is a neurocutaneous syndrome that can ...

[A case of neurofibromatosis type I associated with basal meningocele and abnormal vessels].

PubMed

Yoshioka, H; Sakoda, K; Kohno, H; Hada, H; Hanaya, R; Arita, K; Kurisu, K

1998-03-01

A 21-year-old man with neurofibromatosis type 1 (NF 1) had many widespread cutaneous neurofibroma on his right face. Magnetic resonance imaging (MRI) revealed basal meningocele due to dysplasia of the skull base. Carotid and vertebral angiograms revealed occlusion of the right internal carotid artery, persistent primitive trigeminal artery. We have reviewed the clinical and radiographic features of this case of neurofibromatosis, meningocele and cerebral arterial abnormalities. NF associated with both intracranial vascular malformation and meningocele is very rare, and in our case both were thought to arise congenitally as a manifestation of mesodermal dysplasia. Careful follow up using MRI and MR angiography should be performed for such patients.

Dorsal root ganglia volume differentiates schwannomatosis and neurofibromatosis 2.

PubMed

Godel, Tim; Mautner, Victor-Felix; Farschtschi, Said; Pham, Mirko; Schwarz, Daniel; Kronlage, Moritz; Gugel, Isabel; Heiland, Sabine; Bendszus, Martin; Bäumer, Philipp

2018-04-01

Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes, and peripheral neuropathy has been reported in both. We prospectively applied in vivo morphometric measurement of dorsal root ganglia volume in 16 schwannomatosis patients, 14 neurofibromatosis type 2 patients, and 26 healthy controls by magnetic resonance neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3, + 267%; L4, + 235%; L5, + 241%; S1, + 300%; S2, + 242%; Bonferroni-adjusted p < 0.001) but not in schwannomatosis. Dorsal root ganglia may be a vulnerable site in origination of areflexia and sensory loss and a useful diagnostic marker in neurofibromatosis type 2. Ann Neurol 2018;83:854-857. © 2018 American Neurological Association.

Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type 1: Efficacy of Computerized Cognitive Training and Stimulant Medication

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0508 TITLE: Multimodal Intervention Trial for Cognitive Deficits in Neurofibromatosis Type 1: Efficacy of...Computerized Cognitive Training and Stimulant Medication PRINCIPAL INVESTIGATOR: Maria T. Acosta, M.D. CONTRACTING ORGANIZATION: Children’s National Health...database. 15. SUBJECT TERMS Neurofibromatosis, cognition , pediatric, computerized training programs, working memory 16. SECURITY CLASSIFICATION OF: 17

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. Copyright © 2013 Elsevier B.V. All rights reserved.

Neurofibromatosis

MedlinePlus

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

The Rare Togetherness of Bladder Leiomyoma and Neurofibromatosis.

PubMed

Yucel, Cem; Budak, Salih; Kisa, Erdem; Celik, Orcun; Kozacioglu, Zafer

2018-01-01

Neurofibromatosis Type 1 (Von Recklinghausen disease) is a common, autosomal dominant hereditary disorder characterized by involvement of multiple tissues derived from the neural crest. Urinary system involvement in neurofibromatosis is a rare condition. Leiomyoma of the bladder is a rare benign mesenchymal tumor. In this case, our experience and approach regarding the bladder leiomyoma development in a patient diagnosed with neurofibromatosis are presented and the literature data has been reviewed.

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…

[Selected problems of neurofibromatosis with presentation of a case of multiple intracranial and intramedullary tumors].

PubMed

Stachura, Z; Zralek, C; Siemianowicz, S; Kiczka-Zralek, M; Zawadzki, T; Kluczewska, E; Giec-Lorenc, A

1998-01-01

A case of neurofibromatosis type II in a 19-year-old man is described with clinical and neuroimaging (MRI) findings. The diagnostic criteria of neurofibromatosis type I (NF1) and type II (NF2) and the optimal management options are still controversial. The authors suggest that this patient fulfills criteria of neurofibromatosis type II as well as partially neurofibromatosis type I. At present, without molecular analysis of DNA, this assumption can not be verified.

The Rare Togetherness of Bladder Leiomyoma and Neurofibromatosis

PubMed Central

Celik, Orcun; Kozacioglu, Zafer

2018-01-01

Neurofibromatosis Type 1 (Von Recklinghausen disease) is a common, autosomal dominant hereditary disorder characterized by involvement of multiple tissues derived from the neural crest. Urinary system involvement in neurofibromatosis is a rare condition. Leiomyoma of the bladder is a rare benign mesenchymal tumor. In this case, our experience and approach regarding the bladder leiomyoma development in a patient diagnosed with neurofibromatosis are presented and the literature data has been reviewed. PMID:29736289

Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis

PubMed Central

Blakeley, Jaishri O.; Plotkin, Scott R.

2016-01-01

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are tumor-suppressor syndromes. Each syndrome is an orphan disease; however, the tumors that arise within them represent the most common tumors of the nervous system worldwide. Systematic investigation of the pathways impacted by the loss of function of neurofibromin (encoded by NF1) and merlin (encoded by NF2) have led to therapeutic advances for patients with NF1 and NF2. In the syndrome of SWN, the genetic landscape is more complex, with 2 known causative genes (SMARCB1 and LZTR1) accounting for up to 50% of familial SWN patients. The understanding of the molecular underpinnings of these syndromes is developing rapidly and offers more therapeutic options for the patients. In addition, common sporadic cancers harbor somatic alterations in NF1 (ie, glioblastoma, breast cancer, melanoma), NF2 (ie, meningioma, mesothelioma) and SMARCB1 (ie, atypical teratoid/rhabdoid tumors) such that advances in management of syndromic tumors may benefit patients both with and without germline mutations. In this review, we discuss the clinical and genetic features of NF1, NF2 and SWN, the therapeutic advances for the tumors that arise within these syndromes and the interaction between these rare tumor syndromes and the common tumors that share these mutations. PMID:26851632

Neurofibromatosis 2

MedlinePlus

NF2; Bilateral acoustic neurofibromatosis; Bilateral vestibular schwannomas; Central neurofibromatosis ... NF2 include: Brain and spinal tumors Hearing-related (acoustic) tumors Skin tumors Tests include: Physical examination Medical ...

Pheochromocytoma in neurofibromatosis type 1 during pregnancy.

PubMed

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

2017-02-01

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

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.

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. © The Author(s) 2013.

Multidisciplinary surgical management of cherubism complicated by neurofibromatosis type 1.

PubMed

Hachach-Haram, Nadine; Gerarchi, Paul; Benyon, Sarah L; Saggar, Anand; McLellan, Guy; Kirkpatrick, W Niall A

2011-11-01

Cherubism is a rare, autosomal dominant, mostly self-limiting disease of the jaw. It is characterized by bilateral fibrous tissue hyperplasia, giant cell proliferation, and bony degeneration in the lower facial skeleton, which can result in a massive and severely deforming prominence of the maxillomandibular structure. This case study examines the multidisciplinary management of a severe case of cherubism complicated by neurofibromatosis type 1, 2 codominant nonsegregating conditions that were clinically and genetically diagnosed, an extremely rare combination. Adequate mandibular reduction, reconstruction, and dental implantation afforded good restoration of oral function as well as a marked aesthetic improvement. A 14-year-old Fijian girl was referred to our unit for management of severe overgrowth of her mandible that compromised her speech and deglutition. In addition, she displayed clinical features consistent with neurofibromatosis type 1. Radiologic, histologic, and genetic analyses confirmed the diagnosis of both conditions. Our craniofacial multidisciplinary team undertook mandibular reconstruction followed by placement of osseointegrated dental implants. Mandibular reduction, reconstruction, and dental implantation resulted in a significantly improved functional and aesthetic outcome with no further regrowth at 3-year follow-up when she returned to the United Kingdom for osseointegrated dental implant insertion. The successful outcome of this surgically challenging, grossly disfiguring, and rare condition was largely a result of the combined input from our multidisciplinary team, adequate preoperative planning, and the use of a novel surgical technique in debulking and reconstructing her mandible.

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…

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

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.

Therapeutic advances for the tumors associated with neurofibromatosis type 1, type 2, and schwannomatosis.

PubMed

Blakeley, Jaishri O; Plotkin, Scott R

2016-05-01

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are tumor-suppressor syndromes. Each syndrome is an orphan disease; however, the tumors that arise within them represent the most common tumors of the nervous system worldwide. Systematic investigation of the pathways impacted by the loss of function of neurofibromin (encoded byNF1) and merlin (encoded byNF2) have led to therapeutic advances for patients with NF1 and NF2. In the syndrome of SWN, the genetic landscape is more complex, with 2 known causative genes (SMARCB1andLZTR1) accounting for up to 50% of familial SWN patients. The understanding of the molecular underpinnings of these syndromes is developing rapidly and offers more therapeutic options for the patients. In addition, common sporadic cancers harbor somatic alterations inNF1(ie, glioblastoma, breast cancer, melanoma),NF2(ie, meningioma, mesothelioma) andSMARCB1(ie, atypical teratoid/rhabdoid tumors) such that advances in management of syndromic tumors may benefit patients both with and without germline mutations. In this review, we discuss the clinical and genetic features of NF1, NF2 and SWN, the therapeutic advances for the tumors that arise within these syndromes and the interaction between these rare tumor syndromes and the common tumors that share these mutations. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Lower fasting blood glucose in neurofibromatosis type 1

PubMed Central

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

2015-01-01

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

Lower fasting blood glucose in neurofibromatosis type 1.

PubMed

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

2016-01-01

Studies indicate a lower occurrence of diabetes mellitus (DM) in patients with neurofibromatosis type 1 (NF1). Fasting blood glucose (FBG) level is the main criterion used to diagnose DM and glucose intolerance. Therefore, this study compared FBG level between adults with NF1 and non-NF1 controls. We selected clinical records of 57 out of 701 individuals attending the Neurofibromatosis Outpatient Reference Center of the Clinics Hospital of the Federal University of Minas Gerais in Brazil. The selected patients with NF1 were matched to non-NF1 controls selected from the Brazilian Longitudinal Study of Adult Health according to sex, age (range, 35-74 years) and BMI at a ratio of 1:3. In both groups, individuals with DM were excluded. Median FBG level in the NF1 group (86 mg/dl (range, 56-127 mg/dl)) was lower than that in the non-NF1 control group (102 mg/dl (range, 85-146 mg/dl)) (P<0.001). Prevalence of FBG level ≥100 mg/dl in the NF1 group (16%) was lower than that in the non-NF1 control group (63%) (P<0.05). The chance of a high FBG level was 89% lower in the NF1 group (odds ratio, 0.112; 95% CI, 0.067-0.188) (P<0.05). In conclusion, adults with NF1 showed a lower FBG level and a lower prevalence of high FBG level compared with non-NF1 controls. © 2016 The authors.

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…

Anophthalmia: an uncommon manifestation of neurofibromatosis type 1.

PubMed

Chen, Sheng; Pu, Jia-Li; Zhang, Jian-Min; Hong, Yuan

2011-11-01

Neurofibromatosis type 1 (NF-1) is an autosomal dominant, multisystem disorder, affecting approximately 1 of 3500 people. Ocular disorders, such as Lisch nodules, optic gliomas, and anterior segment defects, are typical with clinical presentation. Anophthalmia, as a rare eye malformation, has never been reported in patients with NF-1. We report a 27-year-old patient in whom clinical manifestations of café au lait spots, neurofibromas, osseous orbital dysplasia, and anophthalmia were observed. The diagnosis of NF-1 was made, according to clinical course and brain computed tomography and magnetic resonance imaging. Because the patient refused aggressive management approaches, she was managed conservatively and is well on follow-up. We suggest that patients presenting with anophthalmia need serious evaluation and that NF-1 needs to be considered in the differential diagnosis.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyung Jun; Seon, Hyun Ju, E-mail: sunaura@hanmail.net; Choi, Song

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.

Articulation in schoolchildren and adults with neurofibromatosis type 1.

PubMed

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 NF1 schoolchildren and adults, both phonetically and phonologically. Speech samples were collected from 43 Flemish NF1 patients (14 children and 29 adults), ranging in age between 7 and 53 years, using a standardized speech test in which all Flemish single speech sounds and most clusters occur in all their permissible syllable positions. Analyses concentrated on consonants only and included a phonetic inventory, a phonetic, and a phonological analysis. It was shown that phonetic inventories were incomplete in 16.28% (7/43) of participants, in which totally correct realizations of the sibilants /ʃ/ and/or /ʒ/ were missing. Phonetic analysis revealed that distortions were the predominant phonetic error type. Sigmatismus stridens, multiple ad- or interdentality, and, in children, rhotacismus non vibrans were frequently observed. From a phonological perspective, the most common error types were substitution and syllable structure errors. Particularly, devoicing, cluster simplification, and, in children, deletion of the final consonant of words were perceived. Further, it was demonstrated that significantly more men than women presented with an incomplete phonetic inventory, and that girls tended to display more articulation errors than boys. Additionally, children exhibited significantly more articulation errors than adults, suggesting that although the articulation skills of NF1 patients evolve positively with age, articulation problems do not resolve completely from childhood to adulthood. As such, the articulation errors made by NF1 adults may be regarded as residual articulation disorders. It can be concluded that the

Neurofibromatosis type 2 appears to be a genetically homogeneous disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Narod, S.A.; Parry, D.M.; Parboosingh, J.

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 chromosomemore » 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.« less

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. © 2013 Wiley Periodicals, Inc.

Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1)

ERIC Educational Resources Information Center

Eijk, S.; Mous, S. E.; Dieleman, G. C.; Dierckx, B.; Rietman, A. B.; de Nijs, P. F. A.; ten Hoopen, L. W.; van Minkelen, R.; Elgersma, Y.; Catsman-Berrevoets, C. E.; Oostenbrink, R.; Legerstee, J. S.

2018-01-01

In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)--and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly…

Breast cancer and neurofibromatosis type 1: a diagnostic challenge in patients with a high number of neurofibromas.

PubMed

Da Silva, André Vallejo; Rodrigues, Fabiana Resende; Pureza, Mônica; Lopes, Vania Gloria Silami; Cunha, Karin Soares

2015-03-26

Neurofibromatosis 1 is one of the most common genetic diseases in humans, presenting with multiple neurofibromas and an increased risk of various benign and malignant tumors, including breast cancer. In this paper we report a case of a woman with neurofibromatosis 1 and the challenge associated with detecting an advanced breast cancer because of numerous skin neurofibromas, which were responsible for a substantial delay in cancer diagnosis. Literature concerning the association of neurofibromatosis 1 and breast cancer is reviewed and discussed. Best practice guidelines for breast cancer detection are not sufficient for the screening of neurofibromatosis 1 carriers. A more intensive clinical and imaging approach should be used if the same early detection rate as in non-neurofibromatosis 1 women is to be achieved.

mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma

PubMed Central

Giovannini, Marco; Bonne, Nicolas-Xavier; Vitte, Jeremie; Chareyre, Fabrice; Tanaka, Karo; Adams, Rocky; Fisher, Laurel M.; Valeyrie-Allanore, Laurence; Wolkenstein, Pierre; Goutagny, Stephane; Kalamarides, Michel

2014-01-01

Background Neurofibromatosis type 2 (NF2) is a rare autosomal dominant genetic disorder, resulting in a variety of neural tumors, with bilateral vestibular schwannomas as the most frequent manifestation. Recently, merlin, the NF2 tumor suppressor, has been identified as a novel negative regulator of mammalian target of rapamycin complex 1 (mTORC1); functional loss of merlin was shown to result in elevated mTORC1 signaling in NF2-related tumors. Thus, mTORC1 pathway inhibition may be a useful targeted therapeutic approach. Methods We studied in vitro cell models, cohorts of mice allografted with Nf2−/− Schwann cells, and a genetically modified mouse model of NF2 schwannoma in order to evaluate the efficacy of the proposed targeted therapy for NF2. Results We found that treatment with the mTORC1 inhibitor rapamycin reduced the severity of NF2-related Schwann cell tumorigenesis without significant toxicity. Consistent with these results, in an NF2 patient with growing vestibular schwannomas, the rapalog sirolimus induced tumor growth arrest. Conclusions Taken together, these results constitute definitive evidence that justifies proceeding with clinical trials using mTORC1-targeted agents in selected patients with NF2 and in patients with NF2-related sporadic tumors. PMID:24414536

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, V.; Day, C.P.; Manimaran, N.

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.

Intravenous Remifentanil Analgaesia for an Obstetric Patient with Type I Neurofibromatosis and a Factor V Leiden Mutation

PubMed Central

Gálvez, José L.; Errando, Carlos L.; Serrano, Silvia; Martín-Ayuso, Marga; Valverde-Mantecón, José M.

2017-01-01

Type I neurofibromatosis is characterised by altered skin pigmentation and the growth of benign tumours, particularly along the peripheral nerves and central nervous system. We report a 36-year-old primigravida woman in labour who was admitted to the obstetric suite of the Hospital Sant Joan de Déu, Barcelona, Spain, in 2007 with hypothyroidism, type I neurofibromatosis and a factor V Leiden mutation. Due to a lack of cranial and spinal imaging data, an epidural was not indicated; instead, continuous intravenous remifentanil analgaesia was administered. The remifentanil infusion was self-titrated by the patient using a visual analogue scale, with the dosage ranging from 0.01 to 0.25 μg/kg/minute. Due to rotational dystocia, Kjelland-type forceps were used during the delivery. After birth, the infant was found to have Apgar scores of 9 and 10, with no maternal or neonatal adverse effects observed. Although still controversial, remifentanil may be a successful alternative for analgaesia in similar cases; however, the specific risks and benefits for each patient should be considered prior to administration. PMID:29372092

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.

The importance of pheochromocytoma case detection in patients with neurofibromatosis type 1: A case report and review of literature.

PubMed

Tate, Joshua M; Gyorffy, Janelle B; Colburn, Jeffrey A

2017-01-01

Neurofibromatosis type 1 is a complex, multi-system genetic disorder that is associated with an increased prevalence of pheochromocytoma and paraganglioma compared to the general population, 1.0%-5.7% versus 0.2%-0.6%, respectively. A delay in pheochromocytoma and paraganglioma diagnosis or undiagnosed pheochromocytoma and paraganglioma, as seen in normotensive and asymptomatic patients, may portend a significant morbidity and mortality risk due to excess catecholamine secretion. Currently, there are no generally accepted guidelines of screening for pheochromocytoma and paragangliomas in asymptomatic individuals of this population with approaches and practices varying considerably between physicians. Emerging data suggest benefit in routine pheochromocytoma and paraganglioma screening of all individuals with neurofibromatosis type 1. Herein, we present a case to highlight how routine case detection screening would have identified pheochromocytoma earlier in an active duty military member.

Neurofibromatosis type 2 (NF 2) or schwannomatosis?--Case report study and diagnostic criteria.

PubMed

Radek, Maciej; Tomasik, Bartłomiej; Wojdyn, Maciej; Snopkowska-Wiaderna, Dorota; Błaszczyk, Maciej; Radek, Andrzej

2016-01-01

Neurofibromatosis type 2 (NF2) and schwannomatosis are entities that may, due to the similarity of clinical symptoms, cause diagnostic difficulties. Incidence rate of both diseases is similar and estimated between 1:25,000 and 1:40,000. The genes associated with the development of the aforementioned disorders are located on chromosome 22 and lay in proxmity. Schwannomatosis is characterized by an incomplete penetrance and the risk of its transmission to the offspring is significantly lower than in the case of NF 2. Schwannomatosis clinical characteristic is similar to the NF2, however vestibular schwannomas are not present. Therefore the imaging studies evaluated by an experienced radiologist play a key role in the diagnostic process. Forty two-year-old female hospitalized three times because of the tumors of the spinal canal was admitted to the Department of Neurosurgery and Peripheral Nerve Surgery in 2008 because of the cervical pain syndrome with concomitant headache. She was diagnosed with a schwannomatosis, recently distinguished, the third form of neurofibromatosis. MRI imaging revealed craniocervical junction tumor. Suboccipital craniectomy with concomitant C1-C2 laminectomy was done in order to remove the lesion. After the surgery the patient did not present any deficits in neurological examination and was discharged from hospital in good general condition. The patient was diagnosed with schwannomatosis, recently established neurofibromatosis entity which may resemble NF2 clinically. In patients after the age of 30, in whom we observe multiple schwannomas without the concomitant hearing impairment, the diagnosis of schwannomatosis is very likely. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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. Copyright © 2012 Wiley Periodicals, Inc.

A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype.

PubMed

Yimenicioğlu, Sevgi; Yakut, Ayten; Karaer, Kadri; Zenker, Martin; Ekici, Arzu; Carman, Kürşat Bora

2012-12-01

Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.

Optimizing biologically targeted clinical trials for neurofibromatosis

PubMed Central

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

2014-01-01

Introduction The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Areas covered Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. Expert opinion The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy. PMID:23425047

FDA grants orphan drug status to selumetinib for neurofibromatosis type 1 (NF1) treatment | Center for Cancer Research

Cancer.gov

The U.S. Food and Drug Administration granted orphan drug status in February to selumetinib for use in patients with the genetic disorder neurofibromatosis type 1 (NF1), who often develop tumors of the peripheral nervous system. Receiving orphan drug designation is a helpful step for selumetinib.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Soo Jin; Kim, Chang Won, E-mail: radkim@hanafos.com; Kim, Suk

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.

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…

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

DTIC Science & Technology

2014-08-01

Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis PRINCIPAL INVESTIGATOR: David W. Polly, Jr... Neurofibromatosis 1 and Scoliosis 5b. GRANT NUMBER W81XWH-10-1-0469 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David. W. Polly Jr., MD 5d. PROJECT...dystrophic scoliosis is one of most common skeletal manifestations of Neurofibromatosis type 1. Dystrophic scoliosis has a more progressive and

[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

Neurofibromatosis type 2 (NF2) is a dominantly inherited neuroectodermal syndrome that predispose to the development of tumors of the central and peripheral nervous system. Additional features include eye and skin abnormalities. A 12-year old male with diagnosis of MF2 according to Baser et al and presentation in childhood was included. A comprehensive bibliographic review of evolution of the diagnostic criteria for NF2 in children was performed. The pattern of presentation of NF2 in childhood differs from adulthood in many aspects. Ophthalmologic and skin manifestations, and not an auditory dysfunction, are the most common initial symptoms in prepuberal-onset NF2. The most frequent symptoms and signs at presentation are posterior subcapsular cataract, skin manifestations as NF2 plaques and/or peripheral nerve tumors, and neurological dysfunction related to isolated or multiple cranial nerve deficits (other than nerve VIII), brainstem masses or spinal masses. As sensitivity of diagnostic criteria in children is low, those prepuberal patients with congenital or early-onset cataracts and typical skin manifestations of NF2 should be systematically assessed.

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...ABSTRACT Dystrophic or non-dystrophic forms of scoliosis are skeletal manifestations of Neurofibromatosis type 1 (NF1). Dystrophic scoliosis has a more

Pseudoangiomatous stromal hyperplasia with multinucleated stromal giant cells is neither exceptional in gynecomastia nor characteristic of neurofibromatosis type 1.

PubMed

Pižem, Jože; Velikonja, Mojca; Matjašič, Alenka; Jerše, Maja; Glavač, Damjan

2015-04-01

Six cases of gynecomastia with pseudoangiomatous stromal hyperplasia (PASH) and multinucleated stromal giant cells (MSGC) associated with neurofibromatosis type 1 (NF1) have been reported, and finding MSGC within PASH in gynecomastia has been suggested as being a characteristic of NF1. The frequency of PASH with MSGC in gynecomastia and its specificity for NF1 have not, however, been systematically studied. A total of 337 gynecomastia specimens from 215 patients, aged from 8 to 78 years (median, 22 years) were reevaluated for the presence of PASH with MSGC. Breast tissue samples of 25 patients were analyzed for the presence of an NF1 gene mutation using next generation sequencing. Rare MSGC, usually in the background of PASH, were noted at least unilaterally in 27 (13 %) patients; and prominent MSGC, always in the background of PASH, were noted in 8 (4 %) patients. The NF1 gene was mutated in only 1 (an 8-year-old boy with known NF1 and prominent MSGC) of the 25 tested patients, including 6 patients with prominent MSGC and 19 patients with rare MSGC. MSGC, usually in the background of PASH, are not characteristic of NF1.

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

Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome.

PubMed

Wang, Daphne L; Smith, Kelly B; Esparza, Sonia; Leigh, Fawn A; Muzikansky, Alona; Park, Elyse R; Plotkin, Scott R

2012-12-01

Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis.

Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1.

PubMed

Gutmann, David H

2014-07-29

With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific biologically based therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders. © 2014 American Academy of Neurology.

The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis.

PubMed

Blakeley, Jaishri O; Bakker, Annette; Barker, Anne; Clapp, Wade; Ferner, Rosalie; Fisher, Michael J; Giovannini, Marco; Gutmann, David H; Karajannis, Matthias A; Kissil, Joseph L; Legius, Eric; Lloyd, Alison C; Packer, Roger J; Ramesh, Vijaya; Riccardi, Vincent M; Stevenson, David A; Ullrich, Nicole J; Upadhyaya, Meena; Stemmer-Rachamimov, Anat

2017-06-01

The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses. © 2017 Wiley Periodicals, Inc.

Partial unilateral lentiginosis is mosaic neurofibromatosis type 1 or not?

PubMed

Yaşar, Şirin; Ersanli, Ayşegül; Göktay, Fatih; Aytekin, Sema; Cebeci, Dua; Güneş, Pembegül

2017-01-01

Partial unilateral lentiginosis (PUL) is a rare pigmentation disorder characterized by numerous lentigines with sharp margins in the midline in one or more dermatomes. Its segmental pattern suggests that this presentation accompanied by café-au-lait spots, Lisch nodule or neurofibromas has a close relationship with mosaic neurofibromatosis type 1 or segmental neurofibromatosis (NF) in particular. In a group of 16 patients with PUL, who presented at the dermatology outpatient clinic between 1998 and 2015, an examination was made of consanguineous marriage in the family history, the presence of a similar lesion or NF in first-degree relatives, neurofibroma in the physical examination, the involvement pattern, axillary/inguinal freckling and the presence and number of café-au-lait spots. The ophthalmological examination investigated Lisch nodule and optic glioma. The skeletal system was examined for NF involvement. Of 16 patients, 13 (81.2%) were female and three (18.8%) were male with a mean age of 31.19 years (range, 15-48). There was no family history of PUL in any case. Consanguineous marriage was absent in 15 patients (93.8%). While there were accompanying café-au-lait spots in three patients (18.8%). Lisch nodule was an accompanying finding in three patients (18.8%). Axillary freckling was detected in four (25%) patients. Neurofibroma was found in only one patient. Although café-au-lait spots, axillary freckling, neurofibroma and Lisch nodule were present in a small number of the patients, the presence of the findings may be considered to be specific to NF suggests that PUL is a variant of mosaic NF-1. Genetic studies will help to further elucidate this subject. © 2016 Japanese Dermatological Association.

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.

Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome

PubMed Central

Wang, Daphne L.; Smith, Kelly B.; Esparza, Sonia; Leigh, Fawn A.; Muzikansky, Alona; Park, Elyse R.; Plotkin, Scott R.

2013-01-01

Purpose Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. Methods A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. Results Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). Conclusion Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis. PMID:22878510

Attention to faces in social context in children with neurofibromatosis type 1.

PubMed

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

2018-06-05

To examine visual attention to faces within social scenes in children with neurofibromatosis type 1 (NF1) and typically developing peers. Using eye-tracking technology we investigated the time taken to fixate on a face and the percentage of time spent attending to faces relative to the rest of the screen within social scenes in 24 children with NF1 (17 females, seven males; mean age 10y 4mo [SD 1y 9mo]). Results were compared with those of 24 age-matched typically developing controls (11 females, 13 males; mean age 10y 3mo [SD 2y]). There was no significant between-group differences in time taken to initially fixate on a face (p=0.617); however, children with NF1 spent less time attending to faces within scenes than controls (p=0.048). Decreased attention to faces was associated with elevated autism traits in children with NF1. Children with NF1 spend less time attending to faces than typically developing children when presented in social scenes. Our findings contribute to a growing body of literature suggesting that abnormal face processing is a key aspect of the social-cognitive phenotype of NF1 and appears to be related to autism spectrum disorder traits. Clinicians should consider the impact of reduced attention to faces when designing and implementing treatment programmes for social dysfunction in this population. Children with neurofibromatosis type 1 (NF1) demonstrated atypical gaze behaviour when attending to faces. NF1 gaze behaviour was characterized by normal initial fixation on faces but shorter face dwell time. Decreased attention to faces was associated with elevated autism traits in the sample with NF1. © 2018 Mac Keith Press.

Neurofibromatosis and Schwannomatosis.

PubMed

Plotkin, Scott R; Wick, Antje

2018-02-01

Neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis are a group of related classically inherited but often times sporadic tumor suppressor syndromes. Neuro-oncologists should recognize these syndromes, initiate necessary tests in patients with a clinical suspicion, and support genetic counseling of patients and families. In this review, clinical presentation, diagnostic criteria, day-to-day management including supportive care as well as updates on genetics, and experimental treatment strategies are discussed. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The association between glomus tumors and neurofibromatosis.

PubMed

Harrison, Bridget; Moore, Amy M; Calfee, Ryan; Sammer, Douglas M

2013-08-01

To determine whether an epidemiologic association exists between glomus tumors and neurofibromatosis. Using a pathology database, we established a study cohort consisting of all patients who had undergone excision of a glomus tumor of the hand between 1995 and 2010. We created a control cohort by randomly selecting 200 patients who had undergone excision of a ganglion cyst over the same period. We reviewed medical records for each cohort to identify patients with a diagnosis of neurofibromatosis. We calculated the odds ratio was calculated and performed Fisher's exact test to determine the significance of the association. We identified 21 patients with glomus tumors of the hand. Six of these patients carried the diagnosis of neurofibromatosis (29%). In contrast, no patients in the control group carried the diagnosis of neurofibromatosis. The odds ratio for a diagnosis of neurofibromatosis in association with a glomus tumor compared with controls was 168:1. This study provides evidence of a strong epidemiologic association between glomus tumors and neurofibromatosis. Glomus tumor should be included in the differential diagnosis in neurofibromatosis patients who present with a painful lesion of the hand or finger. Diagnostic III. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

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.

Speech disorders in neurofibromatosis type 1: a sample survey.

PubMed

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

2010-01-01

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. This study serves as a pilot to identify key issues in the speech of NF1 patients. In particular, the aim is to explore further the occurrence and nature of problems associated with speech as perceived by the patients themselves. A questionnaire was sent to 149 patients with NF1 registered at the Department of Genetics, Ghent University Hospital. The questionnaire inquired about articulation, hearing, breathing, voice, resonance and fluency. Sixty individuals ranging in age from 4.5 to 61.3 years returned completed questionnaires and these served as the database for the study. The results of this sample survey were compared with data of the normal population. About two-thirds of participants experienced at least one speech or speech-related problem of any type. Compared with the normal population, the NF1 group indicated more articulation difficulties, hearing impairment, abnormalities in loudness, and stuttering. The results indicate that speech difficulties are an area of interest in the NF1 population. Further research to elucidate these findings is needed.

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study

PubMed Central

Jonas, Rachel K.; Roh, EunJi; Montojo, Caroline A.; Pacheco, Laura A.; Rosser, Tena; Silva, Alcino J.; Bearden, Carrie E.

2016-01-01

Background Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. Methods Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Results Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Conclusions Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1. PMID:28736755

Young adults' experience of living with neurofibromatosis type 1.

PubMed

Hummelvoll, Grete; Antonsen, Kjell Magnus

2013-04-01

Neurofibromatosis Type 1 (NF1) may have many psychosocial consequences for affected adults. More knowledge is needed about the experience of psychosocial aspects in different stages of adulthood. This qualitative study aims to describe the experiences and concerns of persons living with NF1 in the early stages of adulthood. In semi-structured interviews, Norwegian adults with NF1 (n = 15) between 18 and 37 years of age described their experiences and concerns. Interview transcripts were analysed in a both concept and data driven way. Severity of NF1 was assessed from interview data. Our data indicate that many informants have more friends than in childhood, including friends with NF1. An important topic is whether or not to inform others about the NF1 diagnosis . Low self-confidence is common, often related to early school failure and bullying or to visible neurofibromas. The unpredictable development of NF1 causes much concern. The experience of NF1's impact seems less associated with the assessed severity than with social network, relation to the labour market, and psychological factors.

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors.

PubMed

Karmakar, Souvik; Reilly, Karlyne M

2017-01-01

With the recent development of new anticancer therapies targeting the immune system, it is important to understand which immune cell types and cytokines play critical roles in suppressing or promoting tumorigenesis. The role of mast cells in promoting neurofibroma growth in neurofibromatosis type 1 (NF1) patients was hypothesized decades ago. More recent experiments in mouse models have demonstrated the causal role of mast cells in neurofibroma development and of microglia in optic pathway glioma development. We review here what is known about the role of NF1 mutation in immune cell function and the role of immune cells in promoting tumorigenesis in NF1. We also review the therapies targeting immune cell pathways and their promise in NF1 tumors.

Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1.

PubMed

van der Vaart, Thijs; Rietman, André B; Plasschaert, Ellen; Legius, Eric; Elgersma, Ype; Moll, Henriëtte A

2016-01-12

To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures. Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data. Strongest mean score deviations from the reference groups were observed for full-scale intelligence (-1.1 SD), Rey Complex Figure Test delayed recall (-2.0 SD), attention problems (-1.2 SD), and social problems (-1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52-0.81) and Child Behavioral Checklist subscales (r range 0.40-0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits. Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1. © 2015 American Academy of Neurology.

[Anxiety disorders in type 1 neurofibromatosis: A case report].

PubMed

Fekih-Romdhane, F; Othman, S; Sahnoun, C; Helayem, S; Abbes, Z; Bouden, A

2015-09-01

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, is one of the most frequent human genetic diseases, with a prevalence of one case in 3000 births, an autosomal dominant mode of inheritance, and a high rate of new mutations. NF1 has markedly variable clinical expression, with manifestations ranging from mild lesions to several complications and functional impairment. The complications are age-specific. Psychiatric disorders are more frequent in NF1 than in the general population, especially in children. They include dysthymia, depressive mood, anxiety, and personality disorders. Bipolar mood disorders or schizophrenia are rather rare. The majority of studies have focused on physical health and neurocognitive function in NF1, whereas psychiatric disorders associated with this disease remain unclear and poorly documented. This report is based on a clinical case and discusses the relationship between neurofibromatosis type 1 and psychiatric disorders, particularly anxiety disorders. This case concerns a 13-year-old girl, the first child of healthy and non-consanguineous parents. The patient's history showed normal psychomotor and psychoaffective development. Her father and paternal grandmother had isolated café-au-lait spots. In June 2013, a subcutaneous mass appeared in her right thigh. She consulted a neurologist and was explored. The physical examination revealed signs of NF1. She had café-au-lait spots on the trunk and extremities, and a neurofibroma in the right thigh. Bilateral ophthalmic examination revealed multiple Lish nodules. After 1 month, a psychiatric consultation was requested for sad mood and night terrors. Obsessive compulsive disorder and generalized anxiety disorder were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The current psychiatric literature does not provide full explanations of anxiety symptoms associated with NF1. Some authors have tried to explain

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)

Social functioning in adults with neurofibromatosis type 1.

PubMed

Pride, Natalie A; Crawford, Hilda; Payne, Jonathan M; North, Kathryn N

2013-10-01

Neurofibromatosis type 1 (NF1) is a common single-gene disorder characterised by a diverse range of cutaneous, neurological and neoplastic manifestations. It is well recognised that children with NF1 have poor peer interactions and are at risk for deficits in social skills. Few studies, however, have examined social functioning in adults with NF1. We aimed to determine whether adults with NF1 are at greater risk for impairment in social skills and to identify potential risk factors for social skills deficits. We evaluated social skills in 62 adults with NF1 and 39 controls using self-report and observer-report measures of social behaviour. We demonstrate that adults with NF1 exhibit significantly less prosocial behaviour than controls. This deficit was associated with social processing abilities and was more evident in males. The frequency of antisocial behaviour was comparable between the two groups, however was significantly associated with behavioural regulation in the NF1 group. These findings suggest that poor social skills in individuals with NF1 are due to deficits in prosocial behaviour, rather than an increase in antisocial behaviour. This will aid the design of interventions aimed at improving social skills in individuals with NF1. Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification of the neurofibromatosis type 1 gene product

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 themore » 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.« less

Brain metastasis of Wilms tumor with diffuse anaplasia and complex cytogenetic phenotype in a child with neurofibromatosis Type 1.

PubMed

Shvartsbeyn, Marianna; Bassani, Luigi; Mikolaenko, Irina; Wisoff, Jeffrey H

2011-10-01

The authors report the first case of a Wilms tumor (WT) with diffuse anaplasia metastatic to the brain in a 13-year-old girl with a history of neurofibromatosis Type 1. At presentation, the metastatic tumor had radiological features that suggested a meningioma. Histologically it was characterized by striking anaplasia and features similar to the patient's previously resected WT with diffuse anaplasia.

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

SEGMENTAL NEUROFIBROMATOSIS: A REPORT OF 3 CASES

PubMed Central

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

2010-01-01

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

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.

[Neuropsychological performance in neurofibromatosis type 1].

PubMed

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

2017-08-01

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

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

DTIC Science & Technology

2007-01-01

including scoliosis and pseudoarthrosis, which are compounded by osteoporosis and poor bone healing. Corrective orthopaedic intervention often fails...3 - Introduction: A large proportion of patients with Neurofibromatosis Type 1 display skeletal abnormalities including scoliosis and...abnormalities including alterations in bone size and shape, the presence of scoliosis , and a tendency to develop pseudoarthrosis. These skeletal

Neurofibromatosis Specialists

MedlinePlus

... Arkansas Arkansas Children’s Hospital Neuroscience Center • Little Rock, AR Arizona Mayo Clinic Arizona Clinical Genomics • Phoenix, AZ ... IL Arkansas Children’s Hospital Neuroscience Center • Little Rock, AR Boston Children’s Hospital Multidisciplinary Neurofibromatosis Program • Boston, MA ...

Nerve ultrasound shows subclinical peripheral nerve involvement in neurofibromatosis type 2.

PubMed

Telleman, Johan A; Stellingwerff, Menno D; Brekelmans, Geert J; Visser, Leo H

2018-02-01

Neurofibromatosis type 2 (NF2) is mainly associated with central nervous system (CNS) tumors. Peripheral nerve involvement is described in symptomatic patients, but evidence of subclinical peripheral nerve involvement is scarce. We conducted a cross-sectional pilot study in 2 asymptomatic and 3 minimally symptomatic patients with NF2 to detect subclinical peripheral nerve involvement. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). A total of 30 schwannomas were found, divided over 20 nerve segments (33.9% of all investigated nerve segments). All patients had at least 1 schwannoma. Schwannomas were identified with HRUS in 37% of clinically unaffected nerve segments and 50% of nerve segments with normal NCS findings. HRUS shows frequent subclinical peripheral nerve involvement in NF2. Clinicians should consider peripheral nerve involvement as a cause of weakness and sensory loss in the extremities in patients with this disease. Muscle Nerve 57: 312-316, 2018. © 2017 Wiley Periodicals, Inc.

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. Copyright © 2014 by the American Society of Neuroimaging.

Neuropathies in the setting of Neurofibromatosis tumor syndromes: Complexities and opportunities.

PubMed

Schulz, Alexander; Grafe, Peter; Hagel, Christian; Bäumer, Philipp; Morrison, Helen; Mautner, Victor-Felix; Farschtschi, Said

2018-01-01

The term 'Neurofibromatosis' (NF) comprises a group of rare diseases with related clinical presentations but distinct genetic conditions. All currently known types - NF1, NF2 and Schwannomatosis - predispose afflicted individuals to the development of glial cell-derived (gliogenic) tumors. Furthermore, the occurrence of neuropathic symptoms, which add to the overall neurologic disability of patients, has been described in all disease entities. We show that neuropathic symptoms are a common and clinically important, yet infrequently studied feature in the NF spectrum. However, the clinical relevance and respective underlying pathogenesis, varies greatly among the different NF types. In this review, we summarize and interpret the latest basic research findings, as well as clinical observations, in respect of Neurofibromatosis-associated neuropathies. Copyright © 2017 Elsevier Inc. All rights reserved.

Tibial Geometry in Individuals with Neurofibromatosis Type 1 without Anterolateral Bowing of the Lower Leg Using Peripheral Quantitative Computed Tomography

PubMed Central

Stevenson, David A.; Viskochil, David H.; Carey, John C.; Slater, Hillarie; Murray, Mary; Sheng, Xiaoming; D’Astous, Jacques; Hanson, Heather; Schorry, Elizabeth; Moyer-Mileur, Laurie J.

2008-01-01

Introduction Lower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1. Methods Peripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4–18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender). Results Using pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p<0.0001), smaller cortical area (p<0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p<0.0001) compared to controls. Discussion Individuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg. PMID:19118659

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.

Clinical and Molecular Aspects of an Informative Family with Neurofibromatosis Type 1 and Noonan Phenotype

PubMed Central

Stevenson, David A.; Viskochil, David H.; Rope, Alan F.; Carey, John C.

2011-01-01

NF-Noonan syndrome (NFNS) has been described as a unique phenotype, combining manifestations of neurofibromatosis type 1 (NF1) and Noonan syndromes, which are separate syndromes. Potential etiologies of NF-Noonan syndrome include a discrete syndrome of distinct etiology, co-segregation of two mutated common genes, variable clinical expressivity of NF1, and/or allelic heterogeneity. We present an informative family with an unusual NF1 mutation with variable features of NF1 and Noonan syndrome. We hypothesize that an NF1 mutant allele can lead to diagnostic manifestations of Noonan syndrome, supporting the hypothesis that NF1 allelic heterogeneity causes NFNS. PMID:16542390

Germline mutation of CHEK2 in neurofibromatosis 1 and 2: Two case reports.

PubMed

Li, Qiang; Zhao, Feilong; Ju, Yan

2018-06-01

Neurofibromatosis, including type 1 and type 2, is inherited dominant disease that causes serious consequences. The genetic mechanism of these diseases has been described, but germline mutation of checkpoint 2 kinase gene, together with other DNA repair related genes, has not been fully elucidated in the context of neurofibromatosis. In this article, we reported identical germline mutation of CHEK2 gene (p.R180C) in a 7-year-old Tibetan boy with NF1, and in a 12-year-old Chinese girl with NF2. Neurofibromatosis 1 and 2 with CHECK2 gene germline mutation. Both patients underwent operation to obtain tumor tissue, and peripheral blood of their family was tested. Identical germline mutation of CHEK2 gene (p.R180C) was detected in both patients, and germline mutations of POLE, MUTYH and ATR were also detected. This is the first article to describe CHEK2 mutation in both NF1 and NF2. This article highlights a possible role of CHEK2, in association with other germline genetic mutations, in tumorigenesis of NF1 and NF2.

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

DTIC Science & Technology

2009-01-01

Schwannomatosis Aspen, Colorado, 2006. (appended Item 1) 2. Crotti TN, Walsh NC, Barnes GL, Gerstenfeld LC, McHugh KP. Neurofibromin expression...Tumor Foundation, International Consortium for the Molecular and Cellular Biology of NF1, NF2, and Schwannomatosis , Aspen, Colorado, 2006...and Cellular Biology of NF1, NF2, and Schwannomatosis , Aspen, Colorado, 2006. A large proportion of patients with Neurofibromatosis Type 1

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…

Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2

DTIC Science & Technology

2014-05-01

Tumors in Neurofibromatosis 2 PRINCIPAL INVESTIGATOR: James F. Gusella, Ph.D. CONTRACTING ORGANIZATION: Massachusetts General... Neurofibromatosis 2 5a. CONTRACT NUMBER W81XWH-13-1-0093 5b. GRANT NUMBER W81XWH-13-1-0093 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) James F. Gusella, Ph.D...genetic and gene expression changes identified. 15. SUBJECT TERMS Neurofibromatosis 2, meningioma, schwannoma, exome, transcriptome 16. SECURITY

Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I

PubMed Central

Bonatti, Francesco; Adorni, Alessia; Matichecchia, Annalisa; Mozzoni, Paola; Uliana, Vera; Pisani, Francesco; Garavelli, Livia; Graziano, Claudio; Gnoli, Maria; Bigoni, Stefania; Boschi, Elena; Martorana, Davide; Percesepe, Antonio

2017-01-01

Neurofibromatosis type I, a genetic disorder due to mutations in the NF1 gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all NF1 gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype/phenotype correlation was found, confirming previous evidences. PMID:28961165

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 ...

[Eye involvement in neurofibromatosis].

PubMed

Baier, M; Pitz, S

2016-05-01

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

Neurofibromatosis of the head and neck: classification and surgical management.

PubMed

Latham, Kerry; Buchanan, Edward P; Suver, Daniel; Gruss, Joseph S

2015-03-01

Neurofibromatosis is common and presents with variable penetrance and manifestations in one in 2500 to one in 3000 live births. The management of these patients is often multidisciplinary because of the complexity of the disease. Plastic surgeons are frequently involved in the surgical management of patients with head and neck involvement. A 20-year retrospective review of patients treated surgically for head and neck neurofibroma was performed. Patients were identified according to International Classification of Diseases, Ninth Revision codes for neurofibromatosis and from the senior author's database. A total of 59 patients with head and neck neurofibroma were identified. These patients were categorized into five distinct, but not exclusive, categories to assist with diagnosis and surgical management. These categories included plexiform, cranioorbital, facial, neck, and parotid/auricular neurofibromatosis. A surgical classification system and clinical characteristics of head and neck neurofibromatosis is presented to assist practitioners with diagnosis and surgical management of this complex disease. The surgical management of the cranioorbital type is discussed in detail in 24 patients. The importance and safety of facial nerve dissection and preservation using intraoperative nerve monitoring were validated in 16 dissections in 15 patients. Massive involvement of the neck extending from the skull base to the mediastinum, frequently considered inoperable, has been safely resected by the use of access osteotomies of the clavicle and sternum, muscle takedown, and brachial plexus dissection and preservation using intraoperative nerve monitoring. Therapeutic, IV.

Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2

DTIC Science & Technology

2015-05-01

Award Number: W81XWH-13-1-0093 TITLE: Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2 PRINCIPAL INVESTIGATOR: James F...Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2 5a. CONTRACT NUMBER W81XWH-13-1-0093 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...confirm genes and processes that contribute to NF2 tumor formation and assess their effects on cellular phenotypes. 15. SUBJECT TERMS Neurofibromatosis

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.

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…

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

PubMed Central

Lodish, Maya B.; Stratakis, Constantine A.

2010-01-01

Neurofibromatosis type 1 (NF-1) and tuberous sclerosis complex (TSC) are two familial syndromes known as phakomatoses that may be associated with endocrine tumors. These hereditary cutaneous conditions affect the central nervous system and are characterized 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 characteristic tumor 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 tumors as part of these familial syndromes. PMID:20833335

Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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.more » 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.« less

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. Published by Elsevier Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 detectedmore » 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.« less

[Prenatal genetic diagnosis for a fetus with atypical neurofibromatosis type 1 microdeletion].

PubMed

Lin, Shaobin; Wu, Jianzhu; Zhang, Zhiqiang; Ji, Yuanjun; Fang, Qun; Chen, Baojiang; Luo, Yanmin

2016-04-01

To analyze the correlation between atypical neurofibromatosis type 1(NF1) microdeletion and fetal phenotype. Fetal blood sampling was carried out for a woman bearing a fetus with talipes equinovarus. G-banded karyotyping and single nucleotide polymorphism array (SNP-array) were performed on the fetal blood sample. Fluorescence in situ hybridization (FISH) was used to confirm the result of SNP array analysis. FISH assay was also carried out on peripheral blood specimens from the parents to ascertain the origin of mutation. The karyotype of fetus was found to be 46, XY by G-banding analysis. However, a 3.132 Mb microdeletion was detected in chromosome region 17q11.2 by SNP array, which overlaped with the region of NF1 microdeletion syndrome. Analyzing of the specimens from the fetus and its parents with FISH has confirmed it to be a de novo deletion. Talipes equinovarus may be an abnormal sonographic feature of fetus with atypical NF1 microdeletion which can be accurately diagnosed with SNP array.

Oral manifestations in patients with neurofibromatosis type-1: a comprehensive literature review.

PubMed

Javed, Fawad; Ramalingam, Sundar; Ahmed, Hameeda Bashir; Gupta, Bhumija; Sundar, Chalini; Qadri, Talat; Al-Hezaimi, Khalid; Romanos, Georgios E

2014-08-01

Oral health status is jeopardized in patients with neurofibromatosis (NF) type-1 (NF-1). The aim of the present study was to comprehensively review the oral manifestations in NF-1 patients. PubMed/Medline and Google-Scholar databases were explored using different keywords. Reviews, commentaries, letters to Editor and articles published in languages other than English were excluded. Neurofibromas of oral and perioral soft tissues with subsequent periodontitis, impacted and supernumerary teeth, enlarged alveolar process with dental spacing, morphological changes in teeth and class III molar relationship have been reported in NF-1 patients. Plexiform neurofibromas were reported both in oral soft tissue, maxilla and mandible with evidence of malignant transformation in some cases. Facial skeletal abnormalities, including enlargement of mandibular foramen, increased dimensions of the coronoid and sigmoid notches and notching of the posterior border of the mandible have also been reported. Association between dental caries and NF-1 remains unclear. Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.

Genotype Phenotype Relationships in Neurofibromatosis 2

DTIC Science & Technology

2001-10-01

stop (t2187c). 200 unrelated individuals (90 with NF2, 24 controls with schwannomatosis , and 86 unaffected controls) were screened for this change and...Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis . Neurogenetics 2:101-108 (1999) Andrade A under the mentorship of Mia...LB, MacCollin M, Parry D, Kluwe L, Lynch J, Jones D, Gusella J. Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis

Genotype Phenotype Relationships in Neurofibromatosis 2

DTIC Science & Technology

2000-10-01

schwannomatosis , and 86 unaffected controls) were screened for this change and 69 were heterozygous (34.5%). 21 heterozygous specimens from control individuals...Jacoby LB, MacCollin M, Parry D, Kluwe L, Lynch J, Jones D, Gusella J. Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis ...Jones D, Gusella J. Allelic expression of the NF2 gene in neurofibromatosis 2 and schwannomatosis . Neurogenetics 2:101-108 (1999) Kluwe L, Mautner V

Structural Basis of Merlin Tumor Suppressor Functions in Neurofibromatosis-2

DTIC Science & Technology

2013-10-01

Neurofibromatosis -2 PRINCIPAL INVESTIGATOR: Tina Izard CONTRACTING ORGANIZATION: The Scripps Research Institute La Jolla, CA 92037-1000...30September2012-29September2013 4. TITLE AND SUBTITLE Structural Basis of Merlin Tumor Suppressor Functions in Neurofibromatosis -2 5a. CONTRACT...14. ABSTRACT Loss-of-function mutations in the neurofibromatosis -2 (NF2) gene lead to familial and sporadic neurological malignancies in man

[Consanguineous marriage and morbi-mortality, short literature review based on an exceptional association: Usher syndrome and Von Recklinghausen neurofibromatosis].

PubMed

Atipo-Tsiba, Pépin-Williams

2016-01-01

Usher syndrome is defined by the association of a progressive or non-progressive congenital sensorineural hearing loss with variable severity and a gradually blinding pigmentary retinopathy. Von Recklinghausen neurofibromatosis or Neurofibromatosis type 1 is the major clinically form of neurofibromatosis which occurs in approximately 90% of cases. Both types of disease are genetic in origin with very low prevalence. The probability of co-occurrence of these diseases in a single individual is exceptional. Inbreeding, as well as all genetic diseases, increases quite significantly the probability of their occurrence. Consanguineous marriages are still widespread in Maghreb and in some regions of the western African. This observation reports an exceptional case of this association in a 40-year-old man of Mauritanian origin born from a consanguineous union.

Theory of mind in children with Neurofibromatosis Type 1.

PubMed

Payne, Jonathan M; Porter, Melanie; Pride, Natalie A; North, Kathryn N

2016-05-01

Neurofibromatosis Type I (NF1) is a single gene disorder associated with cognitive and behavioral deficits. While there is clear evidence for poorer social outcomes in NF1, the factors underlying reduced social function are not well understood. This study examined theory of mind (ToM) in children with NF1 and unaffected controls. ToM was assessed in children with NF1 (n = 26) and unaffected controls (n = 36) aged 4-12 years using a nonverbal picture sequencing task. The task assessed understanding of ToM (unrealized goals, false belief, pretence, intention), while controlling for social script knowledge and physical cause-and-effect reasoning. Children with NF1 made significantly more errors than unaffected controls on most ToM stories while demonstrating no difficulty sequencing physical cause-and-effect stories. Performance on the picture sequencing task was not related to lower intellectual function, symptoms of attention deficit-hyperactivity disorder (ADHD), or parent ratings of executive function. Results suggest a generalized ToM deficit in children with NF1 that appears to be independent of general cognitive abilities and ADHD symptoms. The study refines understanding of the clinical presentation of NF1 and identifies psychological constructs that may contribute to the higher prevalence of social dysfunction in children with NF1. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report.

PubMed

Skaribas, Ioannis; Calvillo, Octavio; Delikanaki-Skaribas, Evangelia

2011-05-10

Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation. A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%. These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients.

Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report

PubMed Central

2011-01-01

Introduction Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation. Case presentation A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%. Conclusion These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients. PMID:21569290

Visuospatial processing in children with neurofibromatosis type 1

PubMed Central

Clements-Stephens, Amy M.; Rimrodt, Sheryl L.; Gaur, Pooja; Cutting, Laurie E.

2008-01-01

Neuroimaging studies investigating the neural network of visuospatial processing have revealed a right hemisphere network of activation including inferior parietal lobe, dorsolateral prefrontal cortex, and extrastriate regions. Impaired visuospatial processing, indicated by the Judgment of Line Orientation (JLO), is commonly seen in individuals with Neurofibromatosis type 1 (NF-1). Nevertheless, few studies have examined the neural activity associated with visuospatial processing in NF-1, in particular, during a JLO task. This study used functional neuroimaging to explore differences in volume of activation in predefined regions of interest between 13 individuals with NF-1 and 13 controls while performing an analogue JLO task. We hypothesized that participants with NF-1 would show anomalous right hemisphere activation and therefore would recruit regions within the left hemisphere to complete the task. Multivariate analyses of variance were used to test for differences between groups in frontal, temporal, parietal, and occipital regions. Results indicate that, as predicted, controls utilized various right hemisphere regions to complete the task, while the NF-1 group tended to recruit left hemisphere regions. These results suggest that the NF-1 group has an inefficient right hemisphere network. An additional unexpected finding was that the NF-1 group showed decreased volume of activation in primary visual cortex (BA 17). Future studies are needed to examine whether the decrease in primary visual cortex is related to a deficit in basic visual processing; findings could ultimately lead to a greater understanding of the nature of deficits in NF-1 and have implications for remediation. PMID:17988695

Florid cemento-osseous dysplasia and peripheral giant cell granuloma in a patient with neurofibromatosis 1.

PubMed

Sarmento, Dmitry José de Santana; Carvalho, Sérgio Henrique Gonçalves de; Araújo, José Cadmo Wanderley Peregrino de; Carvalho, Marianne de Vasconcelos; Silveira, Éricka Janine Dantas da

2017-01-01

We report a 35-year-old mulatto female patient with neurofibromatosis Type 1 who presented with facial asymmetry. The patient had two lesions: florid cemento-osseous dysplasia associated with peripheral giant cell granuloma. She was referred for surgical treatment of the peripheral giant cell granuloma and the florid cemento-osseous dysplasia was treated conservatively by a multidisciplinary team. So far, no changes have been observed in the patient's clinical status. We observed no recurrence of peripheral giant cell granuloma. To the best of our knowledge, the present case is the first report of a patient with neurofibromatosis Type 1 associated with a giant cell lesion and florid cemento-osseous dysplasia.

[Myxedema coma in a patient with type 1 neurofibromatosis: rare association].

PubMed

Sasazawa, Denise Tieko; Tsukumo, Daniela Miti; Lalli, Cristina Alba

2013-12-01

Myxedema coma, a rare but fatal emergency, is an extreme expression of hypothyroidism. We describe a 51-year-old male patient who has discontinued hypothyroidism treatment 10 months earlier and developed lethargy, edema, and cold intolerance symptoms. He also had a previous diagnosis of neurofibromatosis. After admission, he progressed to respiratory insufficiency and coma. The prompt recognition of the condition, thyroid hormone replacement, and management of the complications (hypoventilation, cardiogenic shock associated with swinging heart, adrenal and renal insufficiency and sepsis), resulted in a favorable evolution.

Preimplantation diagnosis for neurofibromatosis.

PubMed

Verlinsky, Yury; Rechitsky, Svetlana; Verlinsky, Oleg; Chistokhina, Anna; Sharapova, Tatyana; Masciangelo, Christina; Levy, Michael; Kaplan, Brian; Lederer, Kevin; Kuliev, Anver

2002-01-01

Preimplantation genetic diagnosis (PGD) has recently been performed for inherited cancer predisposition determined by p53 tumour suppressor gene mutations, suggesting the usefulness of PGD for late onset disorders with genetic predisposition, including those caused by the germline mutations of other tumour suppressor genes. Here PGD was performed for two couples, one at risk for producing a child with maternally derived neurofibromatosis type I (NF1), and the other with paternally derived neurofibromatosis type II (NF2). The procedure involved a standard IVF protocol, combined with testing of oocytes or embryos prior to their transfer back to the patients. Maternal mutation Trp-->Ter (TGG-->TGA) in exon 29 of the NF1 gene was tested by sequential PCR analysis of the first and second polar bodies, and paternal L141P mutation in exon 4 of the NF2 gene by embryo biopsy at the cleavage stage. In both cases, multiplex nested PCR was applied, involving NF1 and NF2 mutation analysis simultaneously with the 3 and 2 linked markers, respectively. Of 57 oocytes tested in four PGD cycles for NF1 mutation, 26 mutation-free oocytes were detected, from which eight were preselected for transfer, two in each cycle. These produced two clinical pregnancies, one confirmed to be mutation free by chorionic villus sampling but ending in a stillbirth, and the other still ongoing. Of 18 embryos analysed in a cycle performed for NF2 mutation, eight mutation-free embryos were detected, three of which were transferred back to the patient, resulting in a singleton pregnancy and the birth of a mutation-free child. This suggests that PGD is a useful approach for avoiding the birth of children with inherited cancer predisposition, determined by NF1 and NF2 gene mutations.

Non-invasive endothelial function assessment in patients with neurofibromatosis type 1: a cross-sectional study

PubMed Central

2013-01-01

Background Neurofibromatosis type 1 (NF1) is a multi-systemic disease caused by neurofibromin deficiency. The reduced life expectancy of patients with NF1 has been attributed to NF1-associated malignant neoplasms. However, an analysis of death certificates in the USA suggests that vascular disease could be an important cause of early death among these patients. Endothelial dysfunction (ED) is related to vasculopathy and is an early marker of subclinical atherosclerosis. Since neurofibromin has already been demonstrated to affect endothelial cell function, ED may be associated with NF1. The purpose of this study was to assess endothelial function in patients with NF1 using a non-invasive method. Methods NF1 patients and healthy control subjects, aged 18 to 35 years, were included. Subjects were excluded if they had any risk factor for vascular disease or any other condition known to affect endothelial function. Endothelial function was assessed using reactive hyperemia-peripheral arterial tone (RH-PAT) technology. ED was defined as a reactive hyperemia index (RHI) lower than 1.35. Results Four of the 29 (13.8%) NF1 patients and 1 of the 30 (3.3%) healthy volunteers had ED (p = 0.153). RHI medians and interquartile intervals were 1.8 (1.58-2.43) for the NF1 group and 2.02 (1.74 – 2.49) for the control group (p = 0.361). Conclusion The prevalence of ED was similar in NF1 patients and healthy controls. PMID:23497412

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

PubMed

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

2011-02-09

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

Atypical Local Interference Affects Global Processing in Children with Neurofibromatosis Type 1.

PubMed

Payne, Jonathan M; Porter, Melanie A; Bzishvili, Samantha; North, Kathryn N

2017-05-01

To examine hierarchical visuospatial processing in children with neurofibromatosis type 1 (NF1), a single gene disorder associated with visuospatial impairments, attention deficits, and executive dysfunction. We used a modified Navon paradigm consisting of a large "global" shape composed of smaller "local" shapes that were either congruent (same) or incongruent (different) to the global shape. Participants were instructed to name either the global or local shape within a block. Reaction times, interference ratios, and error rates of children with NF1 (n=30) and typically developing controls (n=24) were compared. Typically developing participants demonstrated the expected global processing bias evidenced by a vulnerability to global interference when naming local stimuli without a cost of congruence when naming global stimuli. NF1 participants, however, experienced significant interference from the unattended level when naming both local and global levels of the stimuli. Findings suggest that children with NF1 do not demonstrate the typical human bias of processing visual information from a global perspective. (JINS, 2017, 23, 446-450).

Florid cemento-osseous dysplasia and peripheral giant cell granuloma in a patient with neurofibromatosis 1*

PubMed Central

Sarmento, Dmitry José de Santana; de Carvalho, Sérgio Henrique Gonçalves; de Araújo Filho, José Cadmo Wanderley Peregrino; Carvalho, Marianne de Vasconcelos; da Silveira, Éricka Janine Dantas

2017-01-01

We report a 35-year-old mulatto female patient with neurofibromatosis Type 1 who presented with facial asymmetry. The patient had two lesions: florid cemento-osseous dysplasia associated with peripheral giant cell granuloma. She was referred for surgical treatment of the peripheral giant cell granuloma and the florid cemento-osseous dysplasia was treated conservatively by a multidisciplinary team. So far, no changes have been observed in the patient's clinical status. We observed no recurrence of peripheral giant cell granuloma. To the best of our knowledge, the present case is the first report of a patient with neurofibromatosis Type 1 associated with a giant cell lesion and florid cemento-osseous dysplasia. PMID:28538890

Evidence of chromosomal instability in neurofibromatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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.

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.

Soft tissue management of orbitotemporal neurofibromatosis.

PubMed

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

2013-01-01

The aim of this study was to provide an overview of a single-institution, 30-year surgical experience with the soft tissue management of orbitotemporal neurofibromatosis. Lessons learned are highlighted in case presentations. From 1981 to 2011, all patients who presented to the Chang Gung Memorial Hospital Craniofacial Center with craniofacial neurofibromatosis and orbitotemporal involvement were retrospectively reviewed. The medical records of those patients who underwent surgical correction were reviewed for age, extent of involvement, procedures performed, histologic confirmation, and acute complications. All patients were grouped according to the Jackson Classification. The electronic photobank was queried to evaluate results. Thirty-five patients presented to our center with orbitotemporal neurofibromatosis during the study period. Thirty-one patients underwent surgical management of their disease. The average age was 25 years (range 4 to 57 years). Over half of our patients (n = 18) presented with concomitant disease of the cheek. The 2 most common procedures performed were lateral canthopexy (n = 24) and upper eyelid excision (n = 24). The only acute complication recorded was a postoperative hematoma on the fourth postoperative day following simultaneous lateral canthopexy and upper eyelid excision which required operative evacuation. In orbitotemporal neurofibromatosis, tissue hyperextensibility and tumor weight adversely affect outcomes. Treatment of concomitant disease of the cheek should be prioritized in order to provide periorbital support prior to addressing the delicate structures of the eyelids. Preservation of the lateral canthal unit and levator muscle, despite neurofibroma infiltration, is critical to maximize outcomes following debulking procedures of the eyelid and orbit.

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. Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.

PubMed

Weiss, Brian; Widemann, Brigitte C; Wolters, Pamela; Dombi, Eva; Vinks, Alexander; Cantor, Alan; Perentesis, John; Schorry, Elizabeth; Ullrich, Nicole; Gutmann, David H; Tonsgard, James; Viskochil, David; Korf, Bruce; Packer, Roger J; Fisher, Michael J

2015-04-01

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Orbital schwannomatosis in the absence of neurofibromatosis.

PubMed

Koktekir, Bengu Ekinci; Kim, H Jane; Geske, Mike; Bloomer, Michelle; Vagefi, Reza; Kersten, Robert C

2014-11-01

The aim of this study was to describe 3 cases of primary orbital schwannomatosis without associated systemic neurofibromatosis. This is a retrospective interventional study of 3 patients who presented with multiple, distinct masses in the orbit (n = 3) as well as in the hemiface (n = 1). The clinical presentation, imaging features, surgical procedures, and outcomes were defined. Two women and a man presented with of exophthalmos and diplopia. Pain was the most prominent complaint in 2 patients. None of the patients had associated systemic neurofibromatosis by history or examination. Radiologic evaluation with computed tomography or magnetic resonance imaging of orbit revealed multiple well-demarcated intraconal and extraconal masses. Masses were excised, and histopathology confirmed all masses to be schwannomas. Postoperative follow-up was uneventful with alleviation of primary complaints in all patients. Multiple orbital schwannomas (primary orbital schwannomatosis) may be observed in patients without systemic association of neurofibromatosis. Management includes surgical excision of the tumors to achieve relief from their mass effects.

PCR-based polymorphisms in neurofibromatosis type 1 (NFI)

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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). Anmore » 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.« less

Underlying mechanisms of writing difficulties among children with neurofibromatosis type 1.

PubMed

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

2014-06-01

Writing is a complex activity in which lower-level perceptual-motor processes and higher-level cognitive processes continuously interact. Preliminary evidence suggests that writing difficulties are common to children with Neurofibromatosis type 1 (NF1). The aim of this study was to compare the performance of children with and without NF1 in lower (visual perception, motor coordination and visual-motor integration) and higher processes (verbal and performance intelligence, visual spatial organization and visual memory) required for intact writing; and to identify the components that predict the written product's spatial arrangement and content among children with NF1. Thirty children with NF1 (ages 8-16) and 30 typically developing children matched by gender and age were tested, using standardized assessments. Children with NF1 had a significantly inferior performance in comparison to control children, on all tests that measured lower and higher level processes. The cognitive planning skill was found as a predictor of the written product's spatial arrangement. The verbal intelligence predicted the written content level. Results suggest that high level processes underlie the poor quality of writing product in children with NF1. Treatment approaches for children with NF1 must include detailed assessments of cognitive planning and language skills. Copyright © 2014 Elsevier Ltd. All rights reserved.

Neurofibromatosis-Noonan Syndrome: A Possible Paradigm of the Combination of Genetic and Epigenetic Factors.

PubMed

Yapijakis, Christos; Pachis, Nikos; Voumvourakis, Costas

2017-01-01

Neurofibromatosis-Noonan syndrome (NFNS) is a clinical entity possessing traits of autosomal dominant disorders neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). Germline mutations that disrupt the RAS/MAPK pathway are involved in the pathogenesis of both NS and NF1. In light of a studied Greek family, a new theory for etiological pathogenesis of NFNS is suggested. The NFNS phenotype may be the final result of a combination of a genetic factor (a mutation in the NF1 gene) and an environmental factor with the epigenetic effects of muscle hypotonia (such as hydantoin in the reported Greek family), causing hypoplasia of the face and micrognathia.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 whethermore » 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.« less

Schwannomatosis: the overlooked neurofibromatosis?

PubMed

Koontz, Nicholas A; Wiens, Andrea L; Agarwal, Atul; Hingtgen, Cynthia M; Emerson, Robert E; Mosier, Kristine M

2013-06-01

Schwannomas are typically benign tumors that occur sporadically, in neurofibromatosis type 2 (NF2), or in an entity called "schwannomatosis." Schwannomatosis patients develop multiple schwannomas without involvement of the vestibular apparatus. Geneticists, neurologists, and pathologists have recognized that schwannomatosis is distinct from NF2, but schwannomatosis remains unfamiliar to many radiologists. This article reviews the current medical literature, highlighting the similarities and differences between the schwannomatosis and NF2 phenotypes, genotypes, clinical manifestations, management considerations, and imaging findings. Imaging plays a critical role in diagnosing schwannomatosis, and a basic understanding of this syndrome is of interest to diagnostic radiologists. Moreover, it is imperative that radiologists be able to differentiate schwannomatosis from NF2 on imaging because there are significant differences in the management of these two diseases and clinical outcomes for affected patients.

Abnormal late visual responses and alpha oscillations in neurofibromatosis type 1: a link to visual and attention deficits

PubMed Central

2014-01-01

Background Neurofibromatosis type 1 (NF1) affects several areas of cognitive function including visual processing and attention. We investigated the neural mechanisms underlying the visual deficits of children and adolescents with NF1 by studying visual evoked potentials (VEPs) and brain oscillations during visual stimulation and rest periods. Methods Electroencephalogram/event-related potential (EEG/ERP) responses were measured during visual processing (NF1 n = 17; controls n = 19) and idle periods with eyes closed and eyes open (NF1 n = 12; controls n = 14). Visual stimulation was chosen to bias activation of the three detection mechanisms: achromatic, red-green and blue-yellow. Results We found significant differences between the groups for late chromatic VEPs and a specific enhancement in the amplitude of the parieto-occipital alpha amplitude both during visual stimulation and idle periods. Alpha modulation and the negative influence of alpha oscillations in visual performance were found in both groups. Conclusions Our findings suggest abnormal later stages of visual processing and enhanced amplitude of alpha oscillations supporting the existence of deficits in basic sensory processing in NF1. Given the link between alpha oscillations, visual perception and attention, these results indicate a neural mechanism that might underlie the visual sensitivity deficits and increased lapses of attention observed in individuals with NF1. PMID:24559228

Management of long-term persistent air leakage developed after bullectomy for giant bullous lung disease associated with neurofibromatosis type 1

PubMed Central

Kim, Si-Wook

2016-01-01

Persistent air leakage is a serious and sometimes fatal complication of bullous lung disease surgery. A 32-year-old man with lung involvement of neurofibromatosis type I underwent bullectomy for huge bullae and recurrent pneumothorax. Persistent postoperative air leakage developed and the lung was totally collapsed. The initial surgery failed, but a second trial employing a novel suture technique on half-absorbed polyglycolic acid (PGA) felt successfully resolved the massive air leakage. Pneumothorax did not recur and the patient remained stable without dyspnea. Thus, a suture technique employing half-absorbed PGA felt was an effective option for managing persistent air leakage. PMID:26904244

Adaptive behavior in young children with neurofibromatosis type 1.

PubMed

Klein-Tasman, Bonita P; Colon, Alina M; Brei, Natalie; van der Fluit, Faye; Casnar, Christina L; Janke, Kelly M; Basel, Donald; Siegel, Dawn H; Walker, Jasmine A

2013-01-01

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

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.

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.

Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1.

PubMed

Wimmer, K; Rosenbaum, T; Messiaen, L

2017-04-01

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Spontaneous Hemothorax in Neurofibromatosis Treated with Percutaneous Embolization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arai, Kazunori; Sanada, Junichiro; Kurozumi, Akiko

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 ofmore » 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.« less

Physical therapy as conservative management for cervical pain and headaches in an adolescent with neurofibromatosis type 1: a case study.

PubMed

Helmers, Kristin M; Irwin, Kent E

2009-12-01

: Neurofibromatosis is a group of genetic disorders that affect the development and growth of nerve cell tissues. These disorders include tumors of myelin-producing supportive cells that grow on nerves and can cause changes in bone formation, skin integrity, and nerve transmission. Common musculoskeletal impairments associated with neurofibromatosis type 1 (NF 1) include cervical pain, muscle weakness, muscle stiffness, headaches, and postural deviations. : This case study describes successful physical therapy management and outcomes for cervical pain and headaches in a 17-year-old girl with a 16-year history of NF 1. Difficulties in driving, studying, lifting, and participating in recreational activities were all associated with the patient's pain, decreased cervical range of motion, decreased scapular strength, and postural deviations. : Physical therapy interventions included posture training, dynamic shoulder/scapular strengthening, cervical stabilization, stretching, ultrasound, interferential current, and a progressive home exercise program. : By the end of 13 weeks (20 sessions) of physical therapy, the patient was completely pain free, demonstrated increased cervical range of motion, and had improvements in scapular strength. She returned to full and unrestricted recreational activities, driving, studying, and household chores. Furthermore, scores on the Neck Disability Index improved from 44 of 50 (complete disability) to 2 of 50 (no disability). : Physical therapy may be a viable option for conservative management of musculoskeletal dysfunction and functional limitations resulting from NF 1.

[Aqueductal stenosis in the neurofibromatosis type 1. Presentation of 19 infantile patients].

PubMed

Pascual-Castroviejo, I; Pascual-Pascual, S I; Velázquez-Fragua, R; Viaño, J; Carceller-Benito, F

To present a series of infantile patients with aqueductal stenosis associated with neurofibromatosis type 1 (NF1). Nineteen patients with ages below 16 years, 11 girls and 8 boys, with NF1 presented hydrocephalus due to aqueductal stenosis. All patients, except one who died before the imaging study was performed and was diagnosed by autopsy, were studied by pneumoencephalography (since 1965 to 1974), computerized tomography (CT) (since 1975 to 1984), magnetic resonance (MR) or MR and CT (since 1985 to 2004) (two children had been studied by pneumoencephalography some years before) most times to discard optic pathway tumor and, in few patients, because of intracranial hypertension. All patients showed three ventricular hydrocephalus with aqueductal stenosis. Eleven patients showed optic pathway tumor. One patient had a benign aqueductal tumor that impaired the normal flow of cerebrospinal fluid. Neurological features of hydrocephalus occurred very rapidly in some patients and after several years of evolution in others. Two boys showed precocious puberty. All patients were treated with shunt. In our series, aqueductal stenosis occurred in about 5% of children with NF1. Aqueductal stenosis and hydrocephalus were identified at a short age because many patients were studied suspecting optic pathway tumor. Eleven patients (about 60%) associated optic pathway tumor and aqueductal stenosis.

Asfotase-α improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

PubMed Central

de la Croix Ndong, Jean; Makowski, Alexander James; Uppuganti, Sasidhar; Vignaux, Guillaume; Ono, Koichiro; Perrien, Daniel S.; Joubert, Simon; Baglio, Serena R.; Granchi, Donatella; Stevenson, David A.; Rios, Jonathan J.; Nyman, Jeffry S.; Elefteriou, Florent

2014-01-01

Mineralization of the skeleton depends on the balance between levels of pyrophosphate (PPi), an inhibitor of hydroxyapatite formation, and phosphate generated from PPi breakdown by alkaline phosphatase (ALP). We report here that ablation of Nf1, encoding the RAS/GTPase–activating protein neurofibromin, in bone–forming cells leads to supraphysiologic PPi accumulation, caused by a chronic ERK–dependent increase in genes promoting PPi synthesis and extracellular transport, namely Enpp1 and Ank. It also prevents BMP2–induced osteoprogenitor differentiation and, consequently, expression of ALP and PPi breakdown, further contributing to PPi accumulation. The short stature, impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts could be corrected by enzyme therapy aimed at reducing PPi concentration. These results establish neurofibromin as an essential regulator of bone mineralization, suggest that altered PPi homeostasis contributes to the skeletal dysplasiae associated with neurofibromatosis type-1 (NF1), and that some of the NF1 skeletal conditions might be preventable pharmacologically. PMID:24997609

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.

Evidence of neurofibromatosis type 1 in a multi-morbid Inca child mummy: A paleoradiological investigation using computed tomography

PubMed Central

Wittig, Holger; Zesch, Stephanie; Rosendahl, Wilfried; Blache, Sandra; Müller-Gerbl, Magdalena; Hotz, Gerhard

2017-01-01

Objective In this study, an Inca bundle was examined using computed tomography (CT). The primary aim was to determine the preservation status of bony and soft tissues, the sex, the age at the time of death, possible indicators for disease or even the cause of death, as well as the kind of mummification. A secondary aim was to obtain a brief overview of the wrapping in order to gain additional information on the cultural background. Materials and methods The bundle belongs to the Museum of Cultures in Basel, Switzerland, and was bought in Munich, Germany, in 1921. Radiocarbon dating of the superficial textile yielded a calibrated age between 1480 and 1650 AD. The mummy was investigated using multi-slice CT with slice thickness of 0.75 mm and 110 kilovolt. For standardized assessment of soft tissue preservation, a recently developed checklist was applied. Results CT revealed the mummy of a seven to nine year old boy with superior preservation of bony and soft tissues allowing detailed assessment. Indicators of neurofibromatosis type 1 (paravertebral and cutaneous neurofibromas, a breast neurofibroma, sphenoid wing dysplasia), Chagas disease (dilatation of the esophagus, stomach, rectum, and large amounts of feces), and lung infection (pleural adherence, calcifications), probably due to tuberculosis, were found. Furthermore, signs of peri-mortem violence (transection of the chest and a defect in the abdominal wall) were detected. CT images revealed a carefully performed wrapping. Conclusion CT examination of the Inca bundle proved to be an important non-destructive examination method. Standardized assessment, especially of the soft tissue structures, allowed for diagnoses of several diseases, indicating a multi-morbid child at the time of death. The careful wrapping pointed to a ceremonial burial. Within the cultural background, the signs of fatal violence were discussed as a possible result of war, murder, accident, or human sacrifice. PMID:28403237

[Phenotypic and genetic features in neurofibromatosis type 1 in children].

PubMed

Duat Rodríguez, A; Martos Moreno, G Á; Martín Santo-Domingo, Y; Hernández Martín, A; Espejo-Saavedra Roca, J M; Ruiz-Falcó Rojas, M L; Argente, J

2015-09-01

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease, nevertheless the number of publications providing clinical and genetic data from a significant number of children is limited. The available clinical, epidemiological, radiological and genetic data from 239 children with NF1, who attended at a specialist NF1 clinic between January 2011 and December 2013 were recorded. All the 239 patients had a clinical and/or genetic diagnosis of NF1. The mean age at diagnosis was 2.65±2.85 years. In our series 99.6% met the diagnostic criteria of café au lait spots, 93.7% those of axillary and inguinal freckling, 7.1% showed typical bone lesion, 38.1% neurofibromas, 23% plexiform neurofibromas, 31.4% optic pathway glioma, Lisch nodules were present in 43.1%, and 28% patients had a first degree relative affected with NF1. The NF1 genetic study was performed in 86 patients, and a description of the gene mutations found in 72 of them is presented. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed. The difficulty for clinical diagnosis of NF1 early ages is still evident. Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

Mosaic Neurofibromatosis Type 1 in Children: A Single-Institution Experience.

PubMed

Lara-Corrales, Irene; Moazzami, Mitra; García-Romero, Maria Teresa; Pope, Elena; Parkin, Patricia; Shugar, Andrea; Kannu, Peter

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by loss-of-function mutation in the NF1 gene. Segmental or mosaic NF1 (MNF) is an uncommon presentation of the NF1 result of postzygotic mutations that present with subtle localised clinical findings. Our study's objectives were to describe the clinical characteristics of children with MNF. We conducted a cross-sectional study of children diagnosed with MNF at the Hospital for Sick Children in Toronto, Canada, from January 1992 to September 2012. Data were abstracted from health records and analysed using a standardised data collection form approved by our hospital Research Ethics Board. We identified 60 patients with MNF; 32 of 60 (53.3%) were female. Mean ± SD age at first assessment was 10.6 ± 4.6 years. The most common initial physical manifestation in 39 of 60 (65.0%) patients was localised pigmentary changes only, followed by plexiform neurofibromas only in 10 of 60 (16.7%) and neurofibromas only in 9 of 60 (15.0%). Unilateral findings were seen in 46 of 60 (76.7%) patients. Most common associations identified included learning disabilities (7/60; 12%) and bony abnormalities (6/60; 10.0%). MNF is an underrecognised condition with potential implications for patients. Children mostly present with pigmentary anomalies only. Most patients do not develop associated findings or complications before adulthood, but long-term follow-up will help determine outcomes and possible associations. Recognition and confirmation of the diagnosis is important to provide follow-up and genetic counselling to patients.

Prevalence of sleep disorders in patients with neurofibromatosis type 1.

PubMed

Maraña Pérez, A I; Duat Rodríguez, A; Soto Insuga, V; Domínguez Carral, J; Puertas Martín, V; González Gutiérrez Solana, L

2015-01-01

Neurofibromatosis type 1 (NF1) is frequently associated with neurological disorders unrelated to neurofibromas, including sleep disorders. This article reviews the prevalence of sleep disorders in patients with NF1, compares rates to data reported in the literature, and analyses the relationship between cognitive disorder and attention deficit hyperactivity disorder (ADHD) in these patients. Comparative retrospective study reviewing data collected between January 2010 and January 2012 from patients diagnosed with NF1 in a tertiary hospital. We included 95 paediatric patients with NF1 who completed the Bruni Sleep Disturbance Scale in Children. The overall prevalence of sleep disorders was 6.3%, which was lower than in the general paediatric population. Patients with NF1 and ADHD had a higher prevalence of sleep onset and maintenance disorders (18% vs 6.3%), sleep-wake transition disorders (12.5% vs 6.3%), and daytime sleepiness (12.5% vs 7.9%); differences were not statistically significant. A statistically significant difference was found in the subdomain of nocturnal hyperhidrosis (21.9% vs 6.3%, P < 0.05). Patients with NF1 and IQ<85 showed higher prevalence rates of daytime sleepiness (20% vs 6.7%) and of sleep hyperhidrosis (11% vs 0%). The prevalence of sleep disorders in our cohort of patients with NF1 was no higher than in the general paediatric population, although some of these disorders are more common in cases with cognitive disorders or ADHD. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Neuropsychological profile in Italian children with neurofibromatosis type 1 (NF1) and their relationships with neuroradiological data: Preliminary results.

PubMed

Parmeggiani, A; Boiani, F; Capponi, S; Duca, M; Angotti, M; Pignataro, V; Sacrato, L; Spinardi, L; Vara, G; Maltoni, L; Cecconi, I; Pastore Trossello, M; Franzoni, E

2018-05-04

Neurofibromatosis type 1 is a genetic disorder associated with cognitive deficits, learning disabilities and behavioral problems. These domains appear to have a still controversial debated association with local areas of T2-hyperintensities on MRI images, called unidentified bright objects (UBOs). A cohort of 36 children (aged 7-11 years) included consecutively, underwent neuropsychological and behavioral assessment to determine their cognitive and neuropsychological profile, and the frequency of specific learning disabilities. MRI examination was used to determine the impact of UBOs' presence, number, and location on the cognitive, neuropsychological and behavioral profile, and also the presence of optic glioma. The mean full intelligence quotient was 104.6; only one child had mild intellectual disability. Forty one percent of children had a diagnosis of specific learning disabilities and reading was mainly involved. Twenty per cent had attention problems. All children had normal scores in visuo-motor and visuo-perceptual tests. UBOs were present in 94.0% of the MRI examinations. Two children had optic glioma. Children with UBOs in a specific location and children with UBOs elsewhere were statistically compared, no one of the location seemed to have an impact on general cognition measured with full intelligence quotient. The thalamus was associated with problems in calculation and striatum with behavioral problems. An inverse relationship between the number of UBOs and the full intelligence quotient was present, but without a statistical significance. In this study, the specific location of UBOs did not seem to influence the general cognitive profile and also the relationship between their number and the full intelligence quotient was not significant; these results are still controversial in literature. Finally, the presence of UBOs in the thalamus and striatum may represent a neuroradiological pattern that influences performances in calculation and behavior

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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.

High-frequency ultrasound imaging for cutaneous neurofibroma in patients with neurofibromatosis type I.

PubMed

Raffin, Delphine; Zaragoza, Julia; Georgescou, Gabriella; Mourtada, Youssef; Maruani, Annabel; Ossant, Frédéric; Patat, Frédéric; Vaillant, Loïc; Machet, Laurent

2017-06-01

Neurofibromas (NFs) are benign tumours arising from a nerve sheath, which are present in nearly all patients with neurofibromatosis type 1 (NF1). High-frequency ultrasound (HFU) systems, using frequencies over 20 MHz, were developed to improve visualization of skin tumours by means of increased resolution. To describe NFs by using HFU in patients with NF1. Anonymized HFU (25-MHz) images of NFs were randomized. Initially, two dermatologist investigators, with experience in HFU imaging of the skin, together described the ultrasound images and established eight criteria for NFs. The same task was then repeated by two other dermatologists, also with experience in HFU imaging of the skin, independently, to establish inter-observer agreement. A total of 108 NFs in 29 patients were included. Superficial and subcutaneous NFs were hypoechoic with a round to spindle shape. Plexiform NFs were ill-defined, consisting of multiple hypoechoic linear zones. Good to excellent inter-observer agreement was found for six of the eight criteria (k>0.6). This is the first series describing HFU skin imaging of NFs in patients with NF1. Lateral extension that may correspond to involvement of an adjacent nerve seems to be specific to NFs.

Concurrent Ulcerative Colitis and Neurofibromatosis Type 1: The Question of a Common Pathway.

PubMed

Adams, William; Mitchell, Lisa; Candelaria-Santiago, Roberto; Hefner, Jody; Gramling, Joseph

2016-02-01

Patients with neurofibromatosis type 1 (NF1) are prone to the development of gastrointestinal stromal tumors, which may present clinically with hematochezia, obstruction, or abdominal pain. These symptoms are also commonly associated with the presentation of ulcerative colitis (UC). Within the past 5 years, there have been 2 reports of concurrent NF1 and UC and a common pathophysiologic pathway involving mast cells has been postulated. We present the case of a 15-year-old boy with a known history of NF1 who presented with 3 months of hematochezia and loose stools. A colonoscopy revealed pancolitis and histology demonstrating acute cryptitis, focal crypt abscesses, and architectural distortion consistent with UC. Due to the paucity of reported cases, the findings of both diseases in the same individual could reasonably be discounted as coincidence. However, in light of increasing reports of concurrent NF1 and UC, advances in characterizing the microenvironment within neurofibromas, and recent findings regarding potential shared genetic susceptibility, it is increasingly possible that the proposed common pathway is accurate. Our case adds to the literature and underscores the need for further investigation. Copyright © 2016 by the American Academy of Pediatrics.

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.

Characterization and utilization of an international neurofibromatosis web-based, patient–entered registry: An observational study

PubMed Central

Korf, Bruce; Rangel Miller, Vanessa; Viskochil, David

2017-01-01

The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children’s Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes. PMID:28644838

Characterization and utilization of an international neurofibromatosis web-based, patient-entered registry: An observational study.

PubMed

Seidlin, Mindell; Holzman, Robert; Knight, Pamela; Korf, Bruce; Rangel Miller, Vanessa; Viskochil, David; Bakker, Annette

2017-01-01

The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children's Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes.

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

PubMed

Kresak, Jesse Lee; Walsh, Meggen

2016-06-01

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

Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas

PubMed Central

Karajannis, Matthias A.; Legault, Geneviève; Hagiwara, Mari; Giancotti, Filippo G.; Filatov, Alexander; Derman, Anna; Hochman, Tsivia; Goldberg, Judith D.; Vega, Emilio; Wisoff, Jeffrey H.; Golfinos, John G.; Merkelson, Amanda; Roland, J. Thomas; Allen, Jeffrey C.

2014-01-01

Background Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers. Methods We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m2/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients. Results None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules. Conclusion Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic (“phase 0”) study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors. PMID:24311643

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.

Ocular Alterations in a Rare Case of Segmental Neurofibromatosis Type 1 with a Non-Classified Mutational Variant of the NF-1 Gene.

PubMed

Abdolrahimzadeh, Solmaz; Piraino, Domenica Carmen; Plateroti, Rocco; Scuderi, Gianluca; Recupero, Santi Maria

2016-06-01

Neurofibromatosis type 1 (NF-1) is an autsomal dominant disorder which can occasionally result from somatic mosaicism and manifest as segmental forms of the disease. A 37-year-old woman with ascertained NF-1, based on clinical diagnostic criteria and genetic analysis, was referred for ophthalmological evaluation. Genetic analysis, magnetic resonance imaging (MRI), complete ophthalmological examination, and near infrared reflectance (NIR) images at 815 nm of the retina were obtained. Genetic analysis revealed a non-classified mutational variant of the NF-1 gene identified as NM_000267.3:c2084T > C (p.Leu695Pro.T). MRI demonstrated non-symptomatic bilateral optic nerve gliomas. The only cutaneous sign was a subcutaneous neurofibroma of the posterior cervical region. Slit-lamp examination showed bilateral Lisch nodules. NIR images of the retina did not show any choroidal hamartomas. We report a rare case of segmental neurofibromatosis with a non-classified mutational variant of the NF-1 gene described in only one previous case in the literature. The patient presented with clinical features of NF-1 localized to the head and neck region, compatible with diagnosis of segmental NF-1. Interestingly, ocular manifestations included bilateral optic nerve gliomas and Lisch nodules, but no choroidal hamartomas.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolff, R.K.; Frazer, K.A.; Jackler, R.K.

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,more » 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.« less

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

PubMed

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, we 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, we 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.

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

PubMed Central

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

1992-01-01

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, we 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, we 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. Images Figure 1 Figure 2 PMID:1496981

Safe performance of spinal anesthesia in a critical patient with neurofibromatosis, pectus carinatum, and temporomandibular joint dysfunction: A case report

PubMed Central

2010-01-01

Background Neurofibromatosis is a syndrome caused by the abnormal deposition of neural tissues of the nervous system, endocrine system, visceral structures, and skin. On the other hand, pectus carinatum and temporomandibular joint dysfunction are illnesses that adversly affect the respiratory system and cause additional problems in airway management. Case Presentation Fifty-eight-year-old Turkish male patient had neurofibromatosis, pectus carinatum and temporomandibular joint dysfunction. The case was due to be operated on with the diagnosis of incarcerated umbilical hernia. Spinal anesthesia was successfully performed and the duration of the surgery was 1 hour. No postoperative complications were observed and he was discharged from the hospital on the 3rd post-operative day. Conclusion The anesthetic management of patients with neurofibromatosis requires attention to all possible abnormalities and associated disturbances. Furthermore, the presence of pectus carinatum and temporomandibular joint dysfunction also increase the potential risks. The operation was successfully completed with spinal anesthesia that was carefully applied upon taking the required measures and considering all pathologies that may accompany the case and complications that may occur. PMID:20438631

Corkscrew retinal vessels in neurofibromatosis type 1: report of 12 cases.

PubMed

Muci-Mendoza, R; Ramella, M; Fuenmayor-Rivera, D

2002-03-01

To describe a distinctive spectrum of retinal microvascular abnormalities in 12 patients with neurofibromatosis type 1 (NF-1). This is an observational prospective study of the ocular fundus evaluated by direct ophthalmoscopy with or without fluorescein angiography, to investigate retinal microvascular abnormalities in 32 patients with NF-1 and in 30 control subjects. The evaluation included a complete general and neurological physical examination and in some cases computed tomography, magnetic resonance imaging with gadolinium-DTPA, or both. The occurrence of a distinctive spectrum of retinal microvascular abnormalities is described in 12 patients with NF-1 (37.5%). At the lower end of the spectrum, present in 10 patients, the anomaly consisted of minuscule second or third order tortuous venules, which were called "corkscrew retinal vessels." These were usually isolated but in a few cases multiple. They flow towards the superior or inferior temporal veins. They had a length of one to two disc diameters. They ended either in a minute tuft or vanished on the retinal surface. The upper end of the spectrum was seen in only two patients. One of them had an exceptionally large venous anastomosis on the nasal retina and the other had an arteriovenous malformation extending over one retinal quadrant. None of the patients in the control group had such retinal microvascular abnormalities. The "corkscrew" retinal vessels described in this report constitute a broad spectrum of microvascular markers in NF-1 patients.

Corkscrew retinal vessels in neurofibromatosis type 1: report of 12 cases

PubMed Central

Muci-Mendoza, R; Ramella, M; Fuenmayor-Rivera, D

2002-01-01

Aim: To describe a distinctive spectrum of retinal microvascular abnormalities in 12 patients with neurofibromatosis type 1 (NF-1). Methods: This is an observational prospective study of the ocular fundus evaluated by direct ophthalmoscopy with or without fluorescein angiography, to investigate retinal microvascular abnormalities in 32 patients with NF-1 and in 30 control subjects. The evaluation included a complete general and neurological physical examination and in some cases computed tomography, magnetic resonance imaging with gadolinium-DTPA, or both. Results: The occurrence of a distinctive spectrum of retinal microvascular abnormalities is described in 12 patients with NF-1 (37.5%). At the lower end of the spectrum, present in 10 patients, the anomaly consisted of minuscule second or third order tortuous venules, which were called “corkscrew retinal vessels.” These were usually isolated but in a few cases multiple. They flow towards the superior or inferior temporal veins. They had a length of one to two disc diameters. They ended either in a minute tuft or vanished on the retinal surface. The upper end of the spectrum was seen in only two patients. One of them had an exceptionally large venous anastomosis on the nasal retina and the other had an arteriovenous malformation extending over one retinal quadrant. None of the patients in the control group had such retinal microvascular abnormalities. Conclusion: The “corkscrew” retinal vessels described in this report constitute a broad spectrum of microvascular markers in NF-1 patients. PMID:11864883

Sphenoid dysplasia in neurofibromatosis type 1: a new technique for repair.

PubMed

Concezio, Di Rocco; Amir, Samii; Gianpiero, Tamburrini; Luca, Massimi; Mario, Giordano

2017-06-01

Sphenoid bone dysplasia in neurofibromatosis type 1 is characterized by progressive exophthalmos and facial disfiguration secondary to herniation of meningeal and cerebral structures. We describe a technique for reconstruction of the sphenoid defect apt at preventing or correcting the ocular globe dislocation. After placement of spinal cerebrospinal fluid drainage to reduce intracranial pressure, the temporal pole is posteriorly dislocated extradurally. The greater sphenoid wing defect is identified. A titanium mesh covered by lyophilized dura, modeled in a curved fashion, is interposed between the bone defect and the cerebro-meningeal structures with its convex surface over the retracted temporal pole. The particular configuration of the titanium mesh allows a self-maintaining position due to the pressure exerted by the brain over its convex central part with its lateral margins consequently pushed and self-anchored against the medial and lateral walls of the temporal fossa. Screw fixation is not needed. The technique utilized in four cases proved to be reliable at the long-term clinical and neuroradiological controls (6 to 19 years). Sphenoid bone dysplasia in NF1, resulting in proptosis and exophthalmos, is usually progressive. It can be surgically repaired using a curved titanium mesh with the convexity faced to the temporal pole that is in the opposite fashion from all the techniques previously introduced. When utilized early in life, the technique can prevent the occurrence of the orbital and facial disfiguration.

Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis

PubMed Central

Kresak, Jesse Lee; Walsh, Meggen

2016-01-01

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

Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study.

PubMed

Jonas, Rachel K; Roh, EunJi; Montojo, Caroline A; Pacheco, Laura A; Rosser, Tena; Silva, Alcino J; Bearden, Carrie E

2017-03-01

Neurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits. Youth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Behaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis.

PubMed

Smith, Miriam J; Bowers, Naomi L; Bulman, Michael; Gokhale, Carolyn; Wallace, Andrew J; King, Andrew T; Lloyd, Simon K L; Rutherford, Scott A; Hammerbeck-Ward, Charlotte L; Freeman, Simon R; Evans, D Gareth

2017-01-03

To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation. © 2016 American Academy of Neurology.

Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis

PubMed Central

Smith, Miriam J.; Bowers, Naomi L.; Bulman, Michael; Gokhale, Carolyn; Wallace, Andrew J.; King, Andrew T.; Lloyd, Simon K.L.; Rutherford, Scott A.; Hammerbeck-Ward, Charlotte L.; Freeman, Simon R.

2017-01-01

Objective: To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. Methods: We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. Results: Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. Conclusions: The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation. PMID:27856782

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

Neurofibromatosis type 1 diagnosed in a child based on multiple juvenile xanthogranulomas and juvenile myelomonocytic leukemia.

PubMed

Jans, Sune R R; Schomerus, Eckhard; Bygum, Anette

2015-01-01

An association between juvenile xanthogranuloma (JXG), neurofibromatosis type 1 (NF1), and juvenile myelomonocytic leukemia (JMML) has been described in the literature but has only been documented in approximately 20 cases. We diagnosed a patient with NF1 at 25 months of age, before any cutaneous stigmata of this disease had appeared, because we decided to screen for the NF1 gene mutation because of his presentation with multiple JXGs and moderate macrocephaly (2.5 standard deviations) at 9 months of age and JMML diagnosed at 20 months of age. The child is well today after treatment with chemotherapy and allogenic bone marrow transplantation. With increased awareness, patients with JXG and NF1 who develop symptoms possibly related to JMML, such as paleness, skin bleeding, cough, unexplained fever, and hepatosplenomegaly, should be further evaluated. We also emphasize that multiple JXG lesions can be an early marker of NF1. © 2014 Wiley Periodicals, Inc.

Phenotypic variability among café-au-lait macules in neurofibromatosis type 1.

PubMed

Boyd, Kevin P; Gao, Liyan; Feng, Rui; Beasley, Mark; Messiaen, Ludwine; Korf, Bruce R; Theos, Amy

2010-09-01

Café-au-lait macules (CALMs) in neurofibromatosis type 1 (NF1) are an early and accessible phenotype in NF1, but have not been extensively studied. We sought to more fully characterize the phenotype of CALMs in patients with NF1. In all, 24 patients with a diagnosis of NF1 confirmed through clinical diagnosis or molecular genetic testing were recruited from patients seen in the genetics department at the University of Alabama at Birmingham. CALM locations were mapped using standard digital photography. Pigment intensity was measured with a narrowband spectrophotometer, which estimates the relative amount of melanin based on its absorption of visible light. The major response was defined as the difference between the mean melanin from the CALM and the mean melanin from the surrounding skin. The major response for each spot was compared with spots within an individual and across individuals in the study population. There was significant variability of the major response, primarily attributable to intrapersonal variability (48.4%, P < .0001) and secondly to interpersonal variability (33.0%, P < .0094). Subsequent analysis based on genetic mutation type showed significantly darker spots in individuals with germline mutations leading to haploinsufficiency. The study was performed on a small population of patients and the method has not yet been used extensively for this purpose. CALMs vary in pigment intensity not only across individuals, but also within individuals and this variability was unrelated to sun exposure. Further studies may help elucidate the molecular basis of this finding, leading to an increased understanding of the pathogenesis of CALMs in NF1. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elyakim, S.; Lerer, I.; Zlotogora, J.

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.more » 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.« less

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

PubMed

Dobran, Mauro; 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.

Pharmacotherapy of attention deficit in neurofibromatosis type 1: effects on cognition.

PubMed

Lidzba, Karen; Granstroem, Sofia; Leark, Robert A; Kraegeloh-Mann, Inge; Mautner, Victor-Felix

2014-08-01

 Attention deficit with or without hyperactivity (AD[H]D) is a common comorbidity of neurofibromatosis type 1 (NF 1). We tested the hypothesis that permanent medication with methylphenidate can improve cognitive functioning in children with NF 1 and comorbid AD(H)D.  We retrospectively analyzed data of a clinical sample of patients with NF 1 with or without AD(H)D, who underwent standardized neuropsychological diagnostics twice (age range: T1, 6-14 years; T2, 7-16 years; mean interval, 49.09 months). A total of 16 children without AD(H)D (nine females) were compared with 14 unmedicated children with AD(H)D (eight females) and to 13 medicated children with AD(H)D (two females). Effects of medication and attention on cognitive outcome (IQ) were tested by repeated measures analysis of covariance (rmANCOVA).  Medicated children with NF 1 improved significantly in full-scale IQ from T1 to T2 (IQ[T1] = 80.38, IQ[T2] = 98.38, confidence interval [diff]: -25.59 to -10.40, p < 0.0001), this effect was not evident for the other groups. With attention measures as covariates, the effect remained marginally significant.  Children and adolescents with NF 1 and comorbid AD(H)D may profit from MPH medication regarding general cognition. This effect could be specific for the group of patients with NF 1, and cannot be explained solely by improvements in attention. Controlled, prospective studies are warranted to corroborate our findings. Georg Thieme Verlag KG Stuttgart · New York.

Association Between Juvenile Myelomonocytic Leukemia, Juvenile Xanthogranulomas and Neurofibromatosis Type 1: Case Report and Review of the Literature.

PubMed

Paulus, Samuel; Koronowska, Sandra; Fölster-Holst, Regina

2017-03-01

The occurrence of juvenile myelomonocytic leukemia (JMML), juvenile xanthogranuloma (JXG), and neurofibromatosis type 1 (NF1) together is relatively rare. Approximately only 20 cases have been reported in the literature. It is debated whether children with NF1 and JXG are at higher risk of developing JMML than children with NF1 alone. We present the case of a boy primarily diagnosed with NF1 with coexisting JXG who developed JMML at the age of 22 months. The clinical course from initial presentation to final diagnosis is detailed and the genetic features and hematologic characteristics are discussed. We report this case to underscore the importance of close monitoring of blood count and strict clinical follow-up in children presenting with concurrent NF1 and JXG and provide a possible explanation for this association. © 2017 Wiley Periodicals, Inc.

Mouse Models of Neurofibromatosis 1 and 21

PubMed Central

Gutmann, David H; Giovannini, Marco

2002-01-01

Abstract The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors. PMID:12082543

Neurofibromatosis, pathological fracture and hypervitaminosis-D.

PubMed

Mondal, Rakesh; Nandi, Madhumita; Chandra, P K

2010-10-01

Pathologic fractures in children may be due to various causes. Rarely, it may be the presenting symptom of neurofibromatosis. A misdiagnosis of Rickets and Vitamin D supplementation in such a case may wreak havoc in the form of iatrogenic hypervitaminosis D. We report one such case.

Social functioning and facial expression recognition in children with neurofibromatosis type 1.

PubMed

Allen, T; Willard, V W; Anderson, L M; Hardy, K K; Bonner, M J

2016-03-01

This study examined social functioning and facial expression recognition (FER) in children with neurofibromatosis type 1 (NF1) compared to typically developing peers. Specifically, the current research aimed to identify hypothesised relationships between neurocognitive ability, FER and social functioning. Children, ages 8 to 16, with NF1 (n = 23) and typically developing peers (n = 23) were recruited during regularly scheduled clinic visits and through advertisements on an institutional clinical trials website, respectively. Participants completed a measure of FER, an abbreviated intelligence test and questionnaires regarding their quality of life and behavioural functioning. Parents were also asked to complete questionnaires regarding the social-emotional and cognitive functioning of their child. As expected, there were significant differences between children with NF1 and typically developing peers across domains of social functioning and FER. Within the sample of children with NF1, there were no significant associations observed between cognitive measures, social functioning and facial recognition skills. Children with NF1 exhibited high rates of social impairment and weak FER skills compared to controls. The absence of associations between FER with cognitive and social variables, however, suggests something unique about this skill in children with NF1. Theoretical comparisons are made to children with autism spectrum disorders, as this condition may serve as a potentially useful model in better understanding FER in children with NF1. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

A porcine model of neurofibromatosis type 1 that mimics the human disease.

PubMed

White, Katherine A; Swier, Vicki J; Cain, Jacob T; Kohlmeyer, Jordan L; Meyerholz, David K; Tanas, Munir R; Uthoff, Johanna; Hammond, Emily; Li, Hua; Rohret, Frank A; Goeken, Adam; Chan, Chun-Hung; Leidinger, Mariah R; Umesalma, Shaikamjad; Wallace, Margaret R; Dodd, Rebecca D; Panzer, Karin; Tang, Amy H; Darbro, Benjamin W; Moutal, Aubin; Cai, Song; Li, Wennan; Bellampalli, Shreya S; Khanna, Rajesh; Rogers, Christopher S; Sieren, Jessica C; Quelle, Dawn E; Weimer, Jill M

2018-06-21

Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1+/ex42del miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.

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

PubMed

Pradhan, Dinesh; Kaur, Neeraj; Gami, Ashmita; Hura, Kanwaljeet S; Garg, Garima; Mohanty, Sambit K

2017-01-01

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

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

PubMed Central

Dahlgaard, Katja; Jung, Anita; Qvortrup, Klaus; Clausen, Henrik; Kjaerulff, Ole; Wandall, Hans H.

2012-01-01

Glycosphingolipids (GSLs) are of fundamental importance in the nervous system. However, the molecular details associated with GSL function are largely unknown, in part because of the complexity of GSL biosynthesis in vertebrates. In Drosophila, only one major GSL biosynthetic pathway exists, controlled by the glycosyltransferase Egghead (Egh). Here we discovered that loss of Egh causes overgrowth of peripheral nerves and attraction of immune cells to the nerves. This phenotype is reminiscent of the human disorder neurofibromatosis type 1, which is characterized by disfiguring nerve sheath tumors with mast cell infiltration, increased cancer risk, and learning deficits. Neurofibromatosis type 1 is due to a reduction of the tumor suppressor neurofibromin, a negative regulator of the small GTPase Ras. Enhanced Ras signaling promotes glial growth through activation of phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We find that overgrowth of peripheral nerves in egh mutants is suppressed by down-regulation of the PI3K signaling pathway by expression of either dominant-negative PI3K, the tumor suppressor PTEN, or the transcription factor FOXO in the subperineurial glia. These results show that loss of the glycosyltransferase Egh affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that glycosyltransferases may suppress proliferation. PMID:22493273

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 lesionsmore » 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.« less

Increased Risk of Cerebrovascular Disease Among Patients With Neurofibromatosis Type 1: Population-Based Approach.

PubMed

Terry, Anna R; Jordan, Justin T; Schwamm, Lee; Plotkin, Scott R

2016-01-01

Although neurofibromatosis type 1 (NF1) may be associated with an incompletely understood vasculopathy, relative odds of stroke in this population is not known. Using the 1998 to 2009 US Nationwide Inpatient Sample, we performed a case-control study matching cases of NF1 to controls without such a diagnosis. We then compared the odds of stroke between the 2 groups. We used multivariable logistic regression to adjust for known or suspected confounders. NF1 was associated with younger mean age at the time of stroke (41 versus 48) and a lower prevalence of stroke risk factors among adult patients. Pediatric patients with NF1, however, were more likely to have hypertension. Patients with NF1 were significantly more likely to be diagnosed with any stroke (odds ratio, 1.2; P<0.0001) than the general population. The odds of intracerebral hemorrhage were greatest among hemorrhagic stroke types analyzed (odds ratio, 1.9; P<0.0001). In the pediatric NF1 population, the odds of intracerebral hemorrhage were more dramatically elevated (odds ratio, 8.1; P<0.0001). The odds of ischemic stroke were also increased with NF1 in the pediatric (odds ratio, 3.4; P<0.0001) but not in the adult population. When compared with the general population, the odds of any type of stroke are significantly increased for patients with NF1, both adult and pediatric. This risk is most notable for hemorrhagic strokes although it is also increased for ischemic strokes in children. Physicians should be aware of the increased risk of stroke in this population, and consider stroke as a potential cause of new neurological symptoms. © 2015 American Heart Association, Inc.

A Computed Tomography-Based Comparison of Abnormal Vertebrae Pedicles Between Dystrophic and Nondystrophic Scoliosis in Neurofibromatosis Type 1.

PubMed

Li, Ying; Luo, Ming; Wang, Wengang; Shen, Mingkui; Xu, Genzhong; Gao, Jianbo; Xia, Lei

2017-10-01

To explore the prevalence and distribution of abnormal vertebral pedicles in scoliosis secondary to neurofibromatosis type 1 (NF1-S) and to compare the abnormal vertebrae pedicles between dystrophic and nondystrophic scoliosis. Using computed tomography images, we carefully measured 2652 vertebral pedicles from 56 patients with NF1-S with dystrophic scoliosis and 22 patients with NF1-S with nondystrophic scoliosis. Pedicle morphology was classified as follows: type A, a cancellous channel of >4 mm; type B, a cancellous channel of 2 to 4 mm; type C, a cancellous channel of <2 mm with an entirely cortical channel of ≥2 mm; type D, a cortical channel of <2 mm; or type E, absent pedicle. Types B, C, D, and E were defined as abnormal. The total prevalence of abnormal vertebral pedicles in patients with NF1-S was as high as 67%, with type B comprising 39%, type C comprising 22%, type D comprising 4%, and type E comprising 2%. A significantly greater rate of abnormal pedicles was found in dystrophic scoliosis compared with nondystrophic scoliosis (70% vs. 59%, P < 0.0001). The upper thoracic spine (87%) is the most concentrated region of abnormal pedicles compared with the lower thoracic (73%) and lumbar spine (34%). There is a significantly high prevalence of abnormal pedicles in patients with NF1-S and an increased rate of abnormal pedicles in dystrophic scoliosis compared with nondystrophic ones. The described pedicle classification system could serve as an objective tool to guide preoperative assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

Subarachnoid Hemorrhage Because of Distal Superior Cerebellar Artery Dissection in Neurofibromatosis Type 1.

PubMed

Takeshima, Yuki; Ohmori, Yuki; Nakagawa, Takashi; Kaku, Yasuyuki; Kuratsu, Jun-Ichi; Yano, Shigetoshi

2017-09-01

Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of 1 in every 3000 births. Numerous studies have focused on the main function of NF1 as a tumor suppressor, whereas few have examined the cerebrovascular abnormalities observed in patients with NF1. It is worth noting that intracranial aneurysms are uncommon in this condition. We report a case of NF1 with a dissection of the distal segment of the superior cerebellar artery. A 36-year-old woman presented with a distal superior cerebellar artery (SCA) dissection causing subarachnoid hemorrhage. Subsequently, because of the rich collateral blood flow distal to the dissection, N-butyl cyanoacrylate (NBCA) glue embolization was unsuccessful. Therefore, direct trapping of the artery was necessary. The patient was discharged after an uneventful postoperative period, and has remained without complications. In the treatment of subarachnoid hemorrhage because of a distal SCA dissection in patients with NF1, NBCA glue embolization may be a safer option than microsurgery or coil embolization, in the acute phase, considering the possible vulnerability of the vessel wall, accessibility, morphology of the lesions, and the risk of developing unpredictable infarcts in the case of parent artery occlusion. However, regular reevaluation of the blood flow is necessary to monitor recurrence, given the rich collateral circulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1

PubMed Central

Tavares, Amelia Brandao; Viveiros, Fernando Arruda; Cidade, Cassilda Neves; Maciel, Jorge

2012-01-01

The gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. These are rare tumours with an incidence of 15 new cases per million per year. The occurrence of neuroendocrine tumours of the pancreas is rare, representing 1–5% of pancreatic cancers, and it is estimated that its incidence does not exceed five to one million. GISTs are common in patients with neurofibromatosis type 1 (NF1); there are few reported cases of synchronous neuroendocrine tumours in these patients and most are pheochromocytomas. The case reports a 64-year-old woman referred to the General Surgery Outpatient for incidental finding of gastric and pancreatic tumours. She underwent a radical subtotal pancreatectomy + partial gastrectomy with jejunal transposition. The pathological examination revealed: gastric GISTs and a well-differentiated neuroendocrine carcinoma of the pancreas. This is the second case published so far of a patient with both tumours  and without NF1. Posterior studies must be performed to evaluate if some other genetic disorder is involved in these patients without NF1. PMID:22675144

Preclinical Mouse Models of Neurofibromatosis

DTIC Science & Technology

2004-10-01

collaborated closely and have shared expertise and reagents extensively. This NF Consortium is a member of the Moue Models of Human Cancer Consortium...of the National Cancer Institute and is participating fully in the activities of the group. The current award will support these collaborative...studies through 2005. 14. SUBJECT TERMS 15. NUMBER OF PAGES Neurofibromatosis, cancer , mouse models 48 16. PRICE CODE 17. SECURITY CLASSIFICATION 78

Optic pathway glioma as part of a constitutional mismatch-repair deficiency syndrome in a patient meeting the criteria for neurofibromatosis type 1.

PubMed

Yeung, Jacky T; Pollack, Ian F; Shah, Sapana; Jaffe, Ronald; Nikiforova, Marina; Jakacki, Regina I

2013-01-01

Patients with constitutional mismatch repair-deficiency (CMMR-D) caused by the biallelic deletions of mismatch repair (MMR) genes have a high likelihood of developing malignancies of the bone marrow, bowel, and brain. Affected individuals often have phenotypic features of neurofibromatosis type 1 (NF-1), including café-au-lait spots. Optic pathway gliomas (OPGs), a common manifestation of NF-1, have not been reported. We report the case of a 3-year-old male with an extensive OPG who met the diagnostic criteria for NF-1. He was subsequently found to have multiple colonic polyps and bi-allelic loss of PMS2. Testing for NF-1 was negative. Copyright © 2012 Wiley Periodicals, Inc.

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders.

PubMed

Evans, D Gareth R; Salvador, Hector; Chang, Vivian Y; Erez, Ayelet; Voss, Stephan D; Druker, Harriet; Scott, Hamish S; Tabori, Uri

2017-06-15

The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1 -related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. ©2017 AACR See all articles in the online-only CCR Pediatric Oncology Series. ©2017 American Association for Cancer Research.

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

PubMed Central

Chabernaud, Camille; Mennes, Maarten; Kardel, Peter G.; Gaillard, William D.; Kalbfleisch, M. Layne; VanMeter, John W.; Packer, Roger J.; Milham, Michael P.; Castellanos, Francisco X.; Acosta, Maria T.

2012-01-01

In the Neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a phase-1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9±2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-minute 3-Tesla echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a Flanker task. After regressing-out task-associated variance, we used the residual time series as “continuous resting-state data” for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model. PMID:22433254

Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2.

PubMed

Winter, Natalie; Rattay, Tim W; Axer, Hubertus; Schäffer, Eva; Décard, Bernhard F; Gugel, Isabel; Schuhmann, Martin; Grimm, Alexander

2017-05-01

The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woods, W.G.; McKenzie, B.; Letourneau, M.A.

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 daysmore » 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.« less

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 highmore » 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.« less

CNS Tumors in Neurofibromatosis.

PubMed

Campian, Jian; Gutmann, David H

2017-07-20

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

Association of pheochromocytoma and ganglioneuroma: unusual finding in neurofibromatosis type 1.

PubMed

Mezitis, Spyros G E; Geller, Mauro; Bocchieri, Elisa; Del Pizzo, Joseph; Merlin, Scott

2007-10-01

To report a rare case of association of pheochromocytoma and ganglioneuroma in an asymptomatic patient with neurofibromatosis type 1 (NF1) and to discuss the importance of annual biochemical and imaging studies. We present the clinical, laboratory, and pathology findings in a 41-year-old woman with NF1 and review the pertinent literature. A 41-year-old woman with NF1 presented for a routine gynecologic examination, at which time a right adrenal mass (4 by 3 cm) was discovered by abdominal ultrasonography and confirmed by abdominal computed tomographic scans and magnetic resonance imaging. The patient was normotensive and complained only of discrete essential tremors. Biochemical studies showed a serum epinephrine level of 195 pg/mL (normal, <100) and a 24-hour urine epinephrine excretion of 55 microg (normal, <20), findings consistent with pheochromocytoma. Metaiodobenzylguanidine scintigraphy revealed uptake in the right adrenal gland, with no evidence of metastatic lesions. Before surgical treatment, the patient received an alpha-adrenergic antagonist for 30 days. Laparoscopic excision of the right adrenal gland yielded excellent postoperative results. Surgical pathology revealed a multinodular mass composed of pheochromocytoma and ganglioneuroma. In patients with NF1 (von Recklinghausen's disease), a tumor consisting of pheochromocytoma and ganglioneuroma is rare and may be more aggressive than pheochromocytoma alone. An asymptomatic catecholamine-producing tumor may cause substantial morbidity and mortality, especially in patients who are undergoing surgical intervention or are under other stressors. The current guidelines for managing patients with NF1 are an annual history and physical examination. Because of the increased prevalence of pheochromocytoma and ganglioneuroma in patients with NF1, and the potential associated adverse effects, we emphasize the importance of periodic clinical evaluation with biochemical testing and imaging studies.

The immunohistochemistry aspects in two cases of neurofibromatosis-associated abdominal tumors.

PubMed

Carşote, Mara; Păun, S; Neamţu, M C; Avramescu, Elena Taina; Iosif, Cristina; Terzea, Dana; Constantinoiu, S; Dănciulescu Miulescu, Ruxandra; Neamţu, Oana Maria; Poiană, Cătălina

2012-01-01

Type 1 neurofibromatosis associates various abdominal tumors as gastrointestinal stromal tumors, duodenal or pancreatic carcinoid, and adrenal tumors like pheochromocytoma. We present the immunohistochemistry report in two cases with different profile regarding the evolution. One case is a 7th decade women diagnosed with unilateral pheochromocytoma and GISTs, with a good prognosis after surgery. The other case is a 41-year-old male diagnosed with duodenal metastatic somatostatinoma after an intestinal occlusive syndrome and later the hormonal profile leaded to the diagnosis of pheochromocytoma. The patient had a fulminate evolution within six months from diagnosis.

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

DTIC Science & Technology

2012-08-01

AD_________________ Award Number: W81XWH-10-1-0469 TITLE: Genetic Evaluation for the Scoliosis ...Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis PRINCIPAL INVESTIGATOR: David W. Polly, Jr., M.D...2011 – 31 July 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Genetic Evaluation for the Scoliosis Gene(s) in Patients with Neurofibromatosis 1

[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.

Clinical presentations of 23 half-siblings from a mosaic neurofibromatosis type 1 sperm donor.

PubMed

Ejerskov, C; Farholt, S; Skovby, F; Vestergaard, E M; Haagerup, A

2016-03-01

The Danish sperm donor number 7042 has fathered several offspring with neurofibromatosis type 1 (NF1) worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene and more than 1000 NF1 mutations are identified. Analysis of the donor sperm demonstrated gonosomal mosaicism with an intragenic deletion involving exons 15-29 in the NF1 gene. At the two Danish reference centres for NF1 patients, we evaluated 23 half-siblings from the donor. Nine were diagnosed with NF1. The severity grade of NF1 progressed from minimal to mild/moderate within 3 years of follow-up. The NF1 phenotype shows great variability in intra- and inter-family expressivity and to date only two NF1 genotype-phenotype correlations have been established. This rare possibility of a long-term follow-up of a cohort of half-siblings with NF1 makes further studies including phenotypic variability and search for modifier genes possible. To achieve this goal, we have initiated The International Donor 7042 NF1 Offspring Registry. Research facilitated via this registry may reveal important new knowledge of clinical characteristics and prognostics for the specific NF1 genotype and thereby contribute to future individualised targeted clinical follow-up and treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bourn, D.; Carter, S.A.; Goodship, J.

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 suggestsmore » that he is a somatic mosaic for the mutation. 26 refs., 3 figs.« less

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

Consensus Recommendations for Current Treatments and Accelerating Clinical Trials for Patients with Neurofibromatosis Type 2

PubMed Central

Blakeley, Jaishri O; Evans, D. Gareth; Adler, John; Brackmann, Derald; Chen, Ruihong; Ferner, Rosalie E.; Hanemann, C. Oliver; Harris, Gordon; Huson, Susan M.; Jacob, Abraham; Kalamarides, Michel; Karajannis, Matthias A.; Korf, Bruce R.; Mautner, Victor-Felix; McClatchey, Andrea I.; Miao, Harry; Plotkin, Scott R.; Slattery, William; Stemmer-Rachamimov, Anat O.; Welling, D. Bradley; Wen, Patrick Y.; Widemann, Brigitte; Hunter-Schaedle, Kim; Giovannini, Marco

2011-01-01

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors. PMID:22140088

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

PubMed

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

2017-07-01

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. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence.

PubMed

Lehtonen, Annukka; Howie, Emma; Trump, Dorothy; Huson, Susan M

2013-02-01

This systematic review aimed to pull together the findings from research into behavioural systems and attention in children with neurofibromatosis type 1 (NF1) and to identify areas that need further study. Relevant papers were identified through searches of electronic databases (MEDLINE, PsycINFO, EMBASE) and manual searches through reference lists. In total, 5746 articles were identified and 57 met the inclusion criteria. The data were synthesized using the narrative approach, as the studies varied considerably in terms of participants and measures. The results of the review showed that intelligence, academic skills, visuospatial skills, social competence, and attention are impaired in children with NF1. Evidence of deficits in memory, motor functioning, language, and executive functions was less clear. Research has made marked progress in outlining the behavioural phenotype of NF1. However, although the general areas of impairment are becoming better known, the exact nature of the impairment is still not understood in many areas of behaviour. Care needs to be taken with the way in which behavioural constructs are defined and measured, and the variability of problems in NF1 is a particular challenge. Nevertheless, research is steadily moving towards comprehensive understanding of behaviour in children with NF1. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

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

PubMed

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

2017-05-01

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

Characterization of early communicative behavior in mouse models of Neurofibromatosis type 1

PubMed Central

Maloney, Susan E.; Chandler, Krystal C.; Anastasaki, Corina; Rieger, Michael A.; Gutmann, David H.; Dougherty, Joseph D.

2017-01-01

Scientific Abstract Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss-of-function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal-separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically-engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/− mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/− mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole-brain serotonin was observed in Nf1+/− mice, but whole-brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD-relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. PMID:28842941

Neurofibromatosis and the role of the specialist adviser.

PubMed

Redman, Carolyn

2017-09-11

Neurofibromatosis (NF) is a genetic condition that mainly involves the nervous system. There are two types: NF1 affects about one in 2,500 of the population worldwide and NF2 affects one in 35,000. Both types result in complex health problems for patients and can pose significant challenges for all those involved in their management. Established in 1981, The Neuro Foundation is a patient-focused charity that funds a network of specialist advisers who work in partnership with the NHS to offer support and advice for families affected by NF and the professionals who care for them. With a significant level of autonomy, the specialist adviser role is flexible in matching the needs of those affected while working cooperatively alongside the national specialist services for NF1 and NF2. ©2012 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

Mobility Functional Outcomes of Neurofibromatosis Patients: A Preliminary Report.

PubMed

Ngo-Huang, An; Yadav, Rajesh; Fu, Jack B; Liu, Diane; Williams, Janet L; Bruera, Eduardo; Guo, Ying

2018-01-01

The aim of the study was to describe the mobility outcomes of neurofibromatosis (NF) patients who received acute inpatient rehabilitation. This is a retrospective study of 62 consecutive neurofibromatosis patients of any age who received physical medicine and rehabilitation consultations at a comprehensive cancer center. Postoperative, inpatient rehabilitation admission and discharge functional independence measures (FIM scores) of transfers and gait and length of hospital stay were obtained from 37 patients who were transferred to inpatient rehabilitation (acute rehabilitation) and 25 who had an alternative disposition (consultation only). Mean age was 34 yrs. Both groups had similar postoperative FIM transfer and gait scores; however, at approximately postoperative day 10, the consultation only group was discharged with median FIM of 5 (supervision level) as compared with the acute rehabilitation group FIM of 4 (P = 0.000). The acute rehabilitation group had improved mobility FIM scores from postoperative to rehabilitation admission and again from rehabilitation admission to discharge (P < 0.0001). At discharge, the acute rehabilitation group ambulated a significantly longer distance (500 f. vs. 300 ft) (P = 0.04). The median length of hospital stay for the acute rehabilitation and consultation only groups was 20 and 10 days, respectively (P = 0.004). Acute inpatient rehabilitation leads to improvement in mobility-associated FIM scores for neurofibromatosis patients minimizing caregiver needs at home.

Dissecting Loss of Heterozygosity (LOH) in Neurofibromatosis Type 1-Associated Neurofibromas: Importance of Copy Neutral LOH

PubMed Central

Garcia-Linares, Carles; Fernández-Rodríguez, Juana; Terribas, Ernest; Mercadé, Jaume; Pros, Eva; Benito, Llúcia; Benavente, Yolanda; Capellà, Gabriel; Ravella, Anna; Blanco, Ignacio; Kehrer-Sawatzki, Hildegard; Lázaro, Conxi; Serra, Eduard

2011-01-01

Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ∼80 kb to ∼8 Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation. Hum Mutat 32:78–90, 2011. © 2010 Wiley-Liss, Inc. PMID:21031597

The spectrum of pheochromocytoma in hypertensive patients with neurofibromatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalff, V.; Shapiro, B.; Lloyd, R.

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 pheochromocytomamore » 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.« less

Case Report: A Rosette-forming Glioneuronal Tumor in the Tectal Plate in a Patient with Neurofibromatosis Type I.

PubMed

Sieg, Emily P; Payne, Russell; Langan, Sara; Specht, Charles S

2016-11-01

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.

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

DTIC Science & Technology

2013-08-01

AD_________________ (Leave blank) Award Number: W81HWH-10-1-0469 TITLE: Genetic Evaluation for the Scoliosis Gene(s) in Patients with...Neurofibromatosis 1 and Scoliosis PRINCIPAL INVESTIGATOR: David W. Polly, Jr., MD CONTRACTING ORGANIZATION: UNIVERSITY OF MINNESOTA Minneapolis, MN 55455...the Scoliosis Gene(s) in Patients with Neurofibromatosis 1 and Scoliosis 5b. GRANT NUMBER W81HWH-10- -0469 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S

Abnormal brain activation in neurofibromatosis type 1: a link between visual processing and the default mode network.

PubMed

Violante, Inês R; Ribeiro, Maria J; Cunha, Gil; Bernardino, Inês; Duarte, João V; Ramos, Fabiana; Saraiva, Jorge; Silva, Eduardo; Castelo-Branco, Miguel

2012-01-01

Neurofibromatosis type 1 (NF1) is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low-level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M) and parvocellular (P) pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified.

Dermabrasion and staged excision of facial lesions in a neurofibromatosis case for improvement of facial appearance.

PubMed

Karabekmez, Furkan Erol; Duymaz, Ahmet; Karacor, Zeynep

2013-01-01

Neurofibromatosis may present with different skin lesions. Disfiguring lesions on the face might be challenging for the surgeon or clinician to correct and may have adverse effects on patients' social lives, especially in young women. To present the dermabrasion technique combined with serial excisions of a deeper accompanying lesion to treat superficial facial lesions in a young neurofibromatosis patient. Dermabrasion was applied to superficial lesions on the face, and staged excision was applied to the deeper lesion located on the forehead. We obtained high patient satisfaction with the result. The deep lesion was excised totally, and superficial lesions were decreased with dermabrasion. Dermabrasion may become a good alternative in cases of neurofibromatosis with superficial facial lesions.

Laryngeal Manifestations of Neurofibromatosis.

PubMed

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

2016-03-01

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

Neurofibromatosis 1 prevalence in children aged 9-11 years, Pinar del Río Province, Cuba.

PubMed

Orraca, Miladys; Morejón, Griselda; Cabrera, Niurka; Menéndez, Reinaldo; Orraca, Odalys

2014-01-01

INTRODUCTION Neurofibromatosis 1 is one of the most common heritable genetic disorders in humans. It is characterized by formation of neurofibromas, with marked variability in expression. Half the cases are due to autosomal dominant inheritance; the rest arise from de novo mutations. Prevalence varies by population, and prevalence in Cuba is unknown. OBJECTIVE Determine the prevalence of neurofibromatosis 1 in a population of Cuban children aged 9-11 years old in Pinar del Río Province, Cuba. METHODS A descriptive cross-sectional study was carried out in Pinar del Río Province in 2004, in which 19,392 children were assessed for neurofibromatosis 1. The study was conducted in two phases: the first, a survey of the entire population aged 9-11 years by genetic counselors in the province's schools; the second, assessment by clinical geneticists of children who met criteria for referral to the Provincial Medical Genetics Center. Neurofibromatosis 1 cases and first-degree relatives were examined to identify the origin of the mutation (de novo or inherited). Neurofibromatosis 1 prevalence was calculated, as well as history of a first-degree relative with the disease and frequency of several principal clinical signs-café au lait spots, freckles in places unexposed to sunlight, presence of neurofibromas, Lisch nodules and characteristic bone lesions. RESULTS Of the eligible population, 99.3% was screened (10,034 boys and 9358 girls). Active case finding resulted in referral of 200 children to medical geneticists and the disease was confirmed in 17, for a prevalence of one case per 1141 children aged 9-11 years old. Café au lait spots were the most frequent sign (100%), followed by freckles in areas unexposed to sunlight (82.4%) and characteristic bone lesions (41.2%). Only 4 of the 17 cases were previously being treated for the disease. CONCLUSIONS Neurofibromatosis 1 has high prevalence in the group studied in Pinar del Rio Province and most cases are not detected in

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.

Worries and needs of adults and parents of adults with neurofibromatosis type 1.

PubMed

Rietman, Andre B; van Helden, Hanneke; Both, Pauline H; Taal, Walter; Legerstee, Jeroen S; van Staa, AnneLoes; Moll, Henriette A; Oostenbrink, Rianne; van Eeghen, Agnies M

2018-05-01

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow-up of adults with NF1 often focuses on tumor growth, follow-up of cognitive or social problems and other NF1-related comorbidity is often not a part of standardized care. In order to provide optimal care services for these patients, we explored the care needs of adults with NF1. A qualitative study was performed using semi-structured group interviews, exploring worries and care needs in medical, psychological, and socioeconomic domains, also focusing on the transition from pediatric to adult care. Four focus groups were conducted, including young adult patients, patients over age 30, and parents of young adult patients. In total, 30 patients and 12 parents participated. Data were transcribed verbatim and analyzed by computerized thematic analysis. Themes were organized using the World Health Organization International classification of functioning, disability, and health (ICF). Results indicated many and diverse worries and care needs both during the transitional period and in adulthood in medical, mental health, and socioeconomic domains. Worries could be categorized into 13 themes. Parents reported high stress levels and difficulties with their parental role. Participants expressed the need for more information, access to NF1 experts, daily living support, care for mental health and socioeconomic participation, and closer communication between health-care providers. In conclusion, worries and needs of patients and parents underline the importance of multidisciplinary follow-up and continuity of care during and after the transitional period. Additionally, parental stress requires more attention from care providers. © 2018 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Posttranscriptional Regulation of the Neurofibromatosis 2 Gene

DTIC Science & Technology

2006-07-01

clinical presenta- tion would be severe and consistent with the con- ventional form of NF2. Schwannomatosis , a recently defined form of neu...rofibromatosis, is characterized by multiple sch- wannomas without any NF2-associated vestibular schwannomas. Patients with schwannomatosis fre- quently...that approximately one-third of patients with schwannomatosis had tumors in an anatomically lim- ited distribution, such as a single limb, several con

Structural Basis of Merlin Tumor Suppressor Functions in Neurofibromatosis-2

DTIC Science & Technology

2014-12-01

Neurofibromatosis-2 PRINCIPAL INVESTIGATOR: Dr. Tina Izard CONTRACTING ORGANIZATION: The Scripps Research Institute Jupiter , FL 33458...ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER The Scripps Research Institute 130 Scripps Way, #2C1 Jupiter , FL 33458

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

Ullrich-Turner syndrome and neurofibromatosis-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 firstmore » 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.« less

Periapical Cemento-osseous Dysplasia Is Rarely Diagnosed on Orthopantomograms of Patients with Neurofibromatosis Type 1 and Is Not a Gender-specific Feature of the Disease.

PubMed

Friedrich, Reinhard E; Reul, Anika

2018-04-01

Several skeletal aberrations of the skull have been described for the tumor predisposition syndrome neurofibromatosis type 1 (NF1). Recently, periapical cemental/cemento-osseous dysplasia (COD) has been described in females affected with NF1. This reactive lesion of the hard tissues in tooth-bearing areas of the jaw has been proposed to represent a gender-specific radiological feature of NF1. The aim of this study was to investigate the prevalence of COD in patients with NF1. The orthopantomograms (OPGs) of 179 patients with a confirmed diagnosis of NF1 were analyzed for COD. The results were compared to radiographic findings obtained in OPGs of age- and sex-matched controls. The NF1 patient group was further differentiated according to the evidence of facial plexiform neurofibroma. COD was a very rare finding in both groups. The extension of the diagnostic criteria including radiologically-healthy teeth and a widened periodontal gap in the periapical area only marginally increased the number of considered cases. Although there was a somewhat more common occurrence of such changes in the patient group compared to the control group and the number of affected women was greater than the number of men, none of these differences reached statistical significance. Furthermore, COD or widening of the periradicular periodontal space was not found to be associated with facial tumor type in NF1. The investigation revealed that COD is not a diagnostic feature of NF1. There is no clear association of the rare finding of COD with gender. These studies should be compared with patient groups of other ethnic backgrounds. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Motor impairment in children with Neurofibromatosis type 1: Effect of the comorbidity with language disorders.

PubMed

Iannuzzi, Stéphanie; Albaret, Jean-Michel; Chignac, Céline; Faure-Marie, Nathalie; Barry, Isabelle; Karsenty, Caroline; Chaix, Yves

2016-02-01

There is a body of evidence demonstrating comorbidity of motor and cognitive deficit in «idiopathic» developmental disorders. These associations are also found in developmental disorders secondary to monogenic disorders as in Neurofibromatosis type 1 for which the principal complication during childhood is learning disabilities. The comparison of motor impairment between developmental disorders either idiopathic or secondary as in NF1 could help us to better understand the cause of the combined language/motor deficit in these populations. The aim of this current study was to investigate motor impairment in children with NF1 for which oral language had been specified and then to compare the motors skills of the NF1 group to motor performance of children with Specific Language Disorder (SLD). Two groups of 49 children between 5 and 12years old were included and compared, the NF1 group and the SLD (Specific Language Disorder) group. Each child completed evaluation involving cognitive, language and motor assessment. In NF1 group, motor impairment was more frequent and more severe and concerned specifically balance rather than manual dexterity or ball skills, compared to a group of children with SLD. This motor impairment was independent of language status in the NF1 group. These results as well as other studies on the same topic could suggest that in NF1 children, fine motor skills impairment would be dependent on the existence of comorbidity with language disorders. Also, that gross motor skills impairment, and more precisely the balance deficit would be characteristic of NF1. This issue encourages studies of procedural learning that can involve the fronto-striatal or the fronto-cerebellar loops according to the type of motor tasks and the stage of learning. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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. © 2016 American Academy of Neurology.

Increased growth rate of vestibular schwannoma after resection of contralateral tumor in neurofibromatosis type 2

PubMed Central

Peyre, Matthieu; Goutagny, Stephane; Imbeaud, Sandrine; Bozorg-Grayeli, Alexis; Felce, Michele; Sterkers, Olivier; Kalamarides, Michel

2011-01-01

Surgical management of bilateral vestibular schwannomas (VS) in neurofibromatosis type 2 (NF2) is often difficult, especially when both tumors threaten the brainstem. When the largest tumor has been removed, the management of the contralateral VS may become puzzling. To give new insights into the growth pattern of these tumors and to determine the best time point for treatment (surgery or medical treatment), we studied radiological growth in 11 VS (11 patients with NF2) over a long period (mean duration, 7.6 years), before and after removal of the contralateral tumor while both were threatening the brainstem. We used a quantitative approach of the radiological velocity of diametric expansion (VDE) on consecutive magnetic resonance images. Before first surgery, growth patterns of both tumors were similar in 9 of 11 cases. After the first surgery, VDE of the remaining VS was significantly elevated, compared with the preoperative period (2.5 ± 2.2 vs 4.4 ± 3.4 mm/year; P = .01, by Wilcoxon test). Decrease in hearing function was associated with increased postoperative growth in 3 cases. Growth pattern of coexisting intracranial meningiomas was not modified by VS surgery on the first side. In conclusion, removal of a large VS in a patient with NF2 might induce an increase in the growth rate of the contralateral medium or large VS. This possibility should be integrated in NF2 patient management to adequately treat the second VS. PMID:21798887

Tandem duplication within a Neurofibromatosis type I (NFI) gene exon in a family with features of Watson syndrome and Noonan syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tassabehji, M.; Strachan, T.; Colley, A.

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 ofmore » 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.« less

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.

Orbital/Peri-Orbital Plexiform Neurofibromas in Children with Neurofibromatosis type 1: Multi-disciplinary Recommendations for Care

PubMed Central

Avery, Robert A.; Katowitz, James A.; Fisher, Michael J.; Heidary, Gena; Dombi, Eva; Packer, Roger J.; Widemann, Brigitte C.

2016-01-01

Children and adults with Neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas involving the eyelid, orbit, periorbital and facial structures (termed OPPN) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. Despite NF1 being a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. While medical and surgical interventions have been reported, there are no agreed upon criteria for when OPPN require therapy and which treatment produces the best outcome. Since a multi-disciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual and or aesthetic sequelae complicates the design of evidence based studies and feasible clinical trials. In September 2013, a multi-disciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. This consensus statement provides recommendations for ophthalmologic monitoring and outlines treatment indications, forthcoming biologic therapy, while also discussing challenges to performing clinical trials in this complicated condition. PMID:27817916

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 germlinemore » 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.« less

Subcellular localization and expression pattern of the neurofibromatosis type 2 protein merlin/schwannomin.

PubMed

Schmucker, B; Ballhausen, W G; Kressel, M

1997-01-01

To elucidate the physiological function of the neurofibromatosis type 2 (NF2) tumor suppressor protein merlin/schwannomin, we studied the expression pattern and subcellular localization in human fibroblasts by Western blot analyses and immunofluorescence using a polyclonal antibody raised against the C-terminus of merlin. Three of the six merlin isoforms identified in this study (75 kDa, 58 kDa, 45 kDa) have been reported earlier and can be explained by alternative splicing. In addition, we detected higher molecular weight bands of about 110 kDa, 100 kDa and 84 kDa. Although the merlin bands of 100 kDa and 110 kDa may represent homo- or heterodimers, oligomerization due to formation of disulfide bonds was excluded. Furthermore, the isoforms of 84 kDa and 58 kDa were quantitatively extractable in Lubrol WX, indicating a localization in or close to the plasma membrane. The 45 kDa band, however, was not soluble in Lubrol WX compatible with a localization of this NF2 isoform in the endoplasmic reticulum. Applying confocal laser scanning microscopy, merlin was shown to be located in four subcellular compartments: (i) perinuclear in a compartment resembling endoplasmic reticulum, (ii) in ruffling membranes and at the leading edges, (iii) in filopodia, and (iv) at cell/substrate adhesion points. Codistribution of merlin and F-actin filaments was found in filopodia, ruffling membranes and at the insertion points of stress fibers at cell/substrate adhesion junctions as shown by phalloidin-rhodamine staining. Double immunofluorescence analyses of merlin and moesin revealed a colocalization in filopodia and ruffling membranes. The localization of merlin in the actin-rich cortical cytoskeleton corresponds to the ezrin-radixin-moesin family of proteins suggesting the NF2 protein to contribute to the regulation of cell growth by interaction with cytoskeleton-associated proteins.

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

Structure-Guided Insights into the Function of Merlin in Neurofibromatosis 2 (NF2)

DTIC Science & Technology

2011-08-01

laboratory of Dr. Lars Pederson (NIEHS-NIH, Research Triangle Park, North Carolina) that harbor entropy mutations on the surface of MBP, and which... mutations . Am J Hum Genet 66: 873–891. 37. Lawrence MC, Colman PM (1993) Shape complementar - ity at protein/protein interfaces. J Mol Biol 234:946–950. 38...Appendices…………………………………………………………………………… 10 3 INTRODUCTION: Neurofibromatosis type 2 (NF2) is caused by inherited or sporadic mutations

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

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.

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

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

PubMed

Drouet, A

2011-12-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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,more » 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.« less

Café-au-lait Macules and Neurofibromatosis Type 1: A Review of the Literature.

PubMed

Bernier, Anne; Larbrisseau, Albert; Perreault, Sebastien

2016-07-01

The first sign of neurofibromatosis type 1 (NF1) in a child is often the presence of multiple café-au-lait macules. Although previous studies reported that almost individuals with multiple café-au-lait macules will eventually develop NF1 based on clinical criteria, recent studies and clinical observations suggest that a significant percentage of them do not have NF1. We conducted the first systematic review of the literature on the prevalence of definitive NF1 among patients referred for isolated café-au-lait macules, searching more precisely for the proportion of those patients who do not have NF1. Because we now know that the presence of café-au-lait macules and freckling might not distinguish between NF1 and other conditions such as Legius syndrome, definitive NF1 was defined as the presence of café-au-lait macules with or without freckling plus one of the following: Lisch nodules, neurofibroma, plexiform neurofibroma, bone dysplasia, optic pathway glioma, or familial history of NF1. Six articles reported sufficient data to meet our inclusion criteria. Grouping all studies together, we found that 19.5% to 57.1% of all patients with isolated café-au-lait macules did not have a diagnosis of NF1 after follow-up or genetic testing. A significant portion of the patients presenting with isolated café-au-lait macules at initial consultation might not have NF1. Genetic testing could help guide the follow-up of those patients, but further evidence is required to make recommendations. Copyright © 2016 Elsevier Inc. All rights reserved.

Resection of a Large Innominate Vein Aneurysm in a Patient with Neurofibromatosis Type 1.

PubMed

Bartline, Peter B; McKellar, Stephen H; Kinikini, Daniel V

2016-01-01

Venous aneurysms are exceedingly rare manifestations of neurofibromatosis type 1 (NF1). There are only a handful of cases reported, and no prior cases describing treatment of mediastinal venous aneurysms in this patient population exist. A 58-year-old woman with NF1 presented with a right neck mass. The mass had recently doubled in size and was associated with cough, hoarseness of voice, and pain. Her pertinent medical history included untreated obstructive sleep apnea, severe pulmonary hypertension, and a recent hospital admission for pneumonia. On physical examination, numerous cutaneous neurofibromas were noted. The mass encompassed her right neck and supraclavicular area with marked respiratory variation. Computed tomography showed a complex 7-cm venous aneurysm including her right innominate, internal jugular, and subclavian veins. Surgical approach involved median sternotomy with right cervical extension and a right infraclavicular counter incision. Extracorporeal circulation was established through the left groin. Ligation of the right internal jugular vein was required. The aneurysm was completely excised, and venous reconstruction consisted of cryopreserved femoral vein anastomosed to right innominate and infraclavicular subclavian veins. Intraoperatively, her preexisting pulmonary hypertension resulted in acute right heart failure requiring placement of a right ventricular assist device (RVAD). She subsequently returned to the operating room for RVAD weaning and sternal closure. Her postoperative course was lengthy; however, many of her aneurysm-related symptoms resolved. This case represents management of the only innominate vein aneurysm in the setting of NF1 described in the literature. Vascular reconstruction is possible, however difficult. Careful preoperative planning and use of extracorporeal circulation was necessary in this case. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic Analyses of the NF1 Gene in Turkish Neurofibromatosis Type I Patients and Definition of three Novel Variants

PubMed Central

Ulusal, SD; Gürkan, H; Atlı, E; Özal, SA; Çiftdemir, M; Tozkır, H; Karal, Y; Güçlü, H; Eker, D; Görker, I

2017-01-01

Abstract Neurofibromatosis Type I (NF1) is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS. PMID:28924536

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2

PubMed Central

Angus, Steve P.; Beauchamp, Roberta L.; Blakeley, Jaishri O.; Bott, Marga; Burns, Sarah S.; Carlstedt, Annemarie; Chang, Long-Sheng; Chen, Xin; Clapp, D. Wade; Desouza, Patrick A.; Erdin, Serkan; Fernandez-Valle, Cristina; Guinney, Justin; Gusella, James F.; Haggarty, Stephen J.; Johnson, Gary L.; Morrison, Helen; Petrilli, Alejandra M.; Plotkin, Scott R.; Pratap, Abhishek; Ramesh, Vijaya; Sciaky, Noah; Stemmer-Rachamimov, Anat; Stuhlmiller, Tim J.; Talkowski, Michael E.; Yates, Charles W.; Zawistowski, Jon S.; Zhao, Wen-Ning

2018-01-01

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype. PMID:29897904

Traditional and systems biology based drug discovery for the rare tumor syndrome neurofibromatosis type 2.

PubMed

Allaway, Robert; Angus, Steve P; Beauchamp, Roberta L; Blakeley, Jaishri O; Bott, Marga; Burns, Sarah S; Carlstedt, Annemarie; Chang, Long-Sheng; Chen, Xin; Clapp, D Wade; Desouza, Patrick A; Erdin, Serkan; Fernandez-Valle, Cristina; Guinney, Justin; Gusella, James F; Haggarty, Stephen J; Johnson, Gary L; La Rosa, Salvatore; Morrison, Helen; Petrilli, Alejandra M; Plotkin, Scott R; Pratap, Abhishek; Ramesh, Vijaya; Sciaky, Noah; Stemmer-Rachamimov, Anat; Stuhlmiller, Tim J; Talkowski, Michael E; Welling, D Bradley; Yates, Charles W; Zawistowski, Jon S; Zhao, Wen-Ning

2018-01-01

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.

Cognitive profile and disorders affecting higher brain functions in paediatric patients with neurofibromatosis type 1.

PubMed

Vaucheret Paz, E; López Ballent, A; Puga, C; García Basalo, M J; Baliarda, F; Ekonen, C; Ilari, R; Agosta, G

2017-04-18

Neurofibromatosis type 1 (NF1) is a common neurocutaneous syndrome often associated with specific cognitive deficits that are rarely monitored during follow-up of these patients. The purpose of our study is two-fold. First, we aimed to describe the cognitive profile of patients with NF1 and detect disorders in higher brain functions associated with the disease. Second, we identified the reasons for consultation associated with school performance in these patients. We conducted a descriptive cross-sectional study of 24 paediatric patients (ages 5 to 16) with NF1 who underwent neuropsychological assessment. The most frequent reasons for consultation were attention deficits (58.33%), learning disorders (25%), poor motor coordination (25%), and language impairment (0.8%). Although 96% of the patients displayed impairments in at least one of the assessed areas, only 83.34% of the parents had reported such impairments. Attention-deficit/hyperactivity disorder was present in 58.33% of the patients, whereas 33.33% had nonverbal learning disabilities, 20.83% had expressive language disorder, 8.33% had borderline intellectual functioning, 4.16% had mental retardation, and only 4.16% showed no cognitive impairment. Higher brain functions are frequently impaired in paediatric patients with NF1. Although many parents report such disorders, they can go undetected in some cases. Neuropsychological assessment is recommended for all paediatric patients with NF1 to detect cognitive impairment and provide early, effective rehabilitation treatment. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Down syndrome and neurofibromatosis: a case report.

PubMed

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

2014-01-01

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

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.

Recognizing schwannomatosis and distinguishing it from neurofibromatosis type 1 or 2.

PubMed

Westhout, Franklin D; Mathews, Marlon; Paré, Laura S; Armstrong, William B; Tully, Patricia; Linskey, Mark E

2007-06-01

Schwannomatosis has become a newly recognized classification of neurofibromatosis. Although the genetic loci are on chromosome 22, it lacks the classic bilateral vestibular schwannomas as seen in NF-2. We present the surgical treatment of 4 patients with schwannomatosis, including a brother and sister. Case 1 presented with multiple progressively enlarging peripheral nerve sheath tumors. Case 4 presented with a trigeminal schwannoma and a vagal nerve schwannoma. Three of 4 patients had spinal intradural, extramedullary nerve sheath tumors. Surgery in all was multistaged and consisted of spinal laminectomies, site-specific explorations, and microsurgical tumor dissection and resection, with intraoperative neurophysiologic monitoring (including somatosensory-evoked and motor-evoked potentials, upper extremity electromyography and intraoperative nerve action potential monitoring, as appropriate). Intraoperatively the schwannomas had cystic and solid features and in all surgical cases the tumors arose from discrete fascicles of sensory nerve roots or sensory peripheral nerve branches. None of the patients experienced neurologic worsening as a result of their resections. Pathologic analysis of specimens from all cases demonstrated schwannoma. Not all patients with multiple schwannomas of cranial nerve, spinal nerve root, or peripheral nerve origin have NF-1 or NF-2. In schwannomatosis, these lesions are present in the absence of cutaneous stigmata, neurofibromas, vestibular schwannomas, or parenchymal brain tumors. Schwannomas in schwannomatosis can be large, cystic, and multiple. However, the predominant nerve involvement seems to be sensory and discrete fascicular in origin, facilitating microsurgical resection with minimal deficit.

Neurofibromatosis type 2 tumor suppressor protein is expressed in oligodendrocytes and regulates cell proliferation and process formation.

PubMed

Toledo, Andrea; Grieger, Elena; Karram, Khalad; Morrison, Helen; Baader, Stephan L

2018-01-01

The neurofibromatosis type 2 (NF2) tumor suppressor protein Merlin functions as a negative regulator of cell growth and actin dynamics in different cell types amongst which Schwann cells have been extensively studied. In contrast, the presence and the role of Merlin in oligodendrocytes, the myelin forming cells within the CNS, have not been elucidated. In this work, we demonstrate that Merlin immunoreactivity was broadly distributed in the white matter throughout the central nervous system. Following Merlin expression during development in the cerebellum, Merlin could be detected in the cerebellar white matter tract at early postnatal stages as shown by its co-localization with Olig2-positive cells as well as in adult brain sections where it was aligned with myelin basic protein containing fibers. This suggests that Merlin is expressed in immature and mature oligodendrocytes. Expression levels of Merlin were low in oligodendrocytes as compared to astrocytes and neurons throughout development. Expression of Merlin in oligodendroglia was further supported by its identification in either immortalized cell lines of oligodendroglial origin or in primary oligodendrocyte cultures. In these cultures, the two main splice variants of Nf2 could be detected. Merlin was localized in clusters within the nuclei and in the cytoplasm. Overexpressing Merlin in oligodendrocyte cell lines strengthened reduced impedance in XCELLigence measurements and Ki67 stainings in cultures over time. In addition, the initiation and elongation of cellular projections were reduced by Merlin overexpression. Consistently, cell migration was retarded in scratch assays done on Nf2-transfected oligodendrocyte cell lines. These data suggest that Merlin actively modulates process outgrowth and migration in oligodendrocytes.

Comparing the sensitivity of linear and volumetric MRI measurements to detect changes in the size of vestibular schwannomas in patients with neurofibromatosis type 2 on bevacizumab treatment.

PubMed

Morris, Katrina A; Parry, Allyson; Pretorius, Pieter M

2016-09-01

To compare the sensitivity of linear and volumetric measurements on MRI in detecting schwannoma progression in patients with neurofibromatosis type 2 on bevacizumab treatment as well as the extent to which this depends on the size of the tumour. We compared retrospectively, changes in linear tumour dimensions at a range of thresholds to volumetric tumour measurements performed using Brainlab iPlan(®) software (Feldkirchen, Germany) and classified for tumour progression according to the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Assessment of 61 schwannomas in 46 patients with a median follow-up of 20 months (range 3-43 months) was performed. There was a mean of 7 time points per tumour (range 2-12 time points). Using the volumetric REiNS criteria as the gold standard, a sensitivity of 86% was achieved for linear measurement using a 2-mm threshold to define progression. We propose that a change in linear measurement by 2 mm (particularly in tumours with starting diameters 20-30 mm, the majority of this cohort) could be used as a filter to identify cases of possible progression requiring volumetric analysis. This pragmatic approach can be used if stabilization of a previously growing schwannoma is sufficient for a patient to continue treatment in such a circumstance. We demonstrate the real-world limitations of linear vs volumetric measurement in tumour response assessment and identify limited circumstances where linear measurements can be used to determine which patients require the more resource-intensive volumetric measurements.

Auditory Brainstem Implantation in Chinese Patients With Neurofibromatosis Type II: The Hong Kong Experience.

PubMed

Thong, Jiun Fong; Sung, John K K; Wong, Terence K C; Tong, Michael C F

2016-08-01

To describe our experience and outcomes of auditory brainstem implantation (ABI) in Chinese patients with Neurofibromatosis Type II (NF2). Retrospective case review. Tertiary referral center. Patients with NF2 who received ABIs. Between 1997 and 2014, eight patients with NF2 received 9 ABIs after translabyrinthine removal of their vestibular schwannomas. One patient did not have auditory response using the ABI after activation. Environmental sounds could be differentiated by six (75%) patients after 6 months of ABI use (mean score 46% [range 28-60%]), and by five (63%) patients after 1 year (mean score 57% [range 36-76%]) and 2 years of ABI use (mean score 48% [range 24-76%]). Closed-set word identification was possible in four (50%) patients after 6 months (mean score 39% [range 12-72%]), 1 year (mean score 68% [range 48-92%]), and 2 years of ABI use (mean score 62% [range 28-100%]). No patient demonstrated open-set sentence recognition in quiet in the ABI-only condition. However, the use of ABI together with lip-reading conferred an improvement over lip-reading alone in open-set sentence recognition scores in two (25%) patients after 6 months of ABI use (mean improvement 46%), and five (63%) patients after 1 year (mean improvement 25%) and 2 years of ABI use (mean improvement 28%). At 2 years postoperatively, three (38%) patients remained ABI users. This is the only published study to date examining ABI outcomes in Cantonese-speaking Chinese NF2 patients and the data seems to show poorer outcomes compared with English-speaking and other nontonal language-speaking NF2 patients. Environmental sound awareness and lip-reading enhancement are the main benefits observed in our patients. More work is needed to improve auditory implant speech-processing strategies for tonal languages and these advancements may yield better speech perception outcomes in the future.

Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis.

PubMed

Louvrier, Camille; Pasmant, Eric; Briand-Suleau, Audrey; Cohen, Joëlle; Nitschké, Patrick; Nectoux, Juliette; Orhant, Lucie; Zordan, Cécile; Goizet, Cyril; Goutagny, Stéphane; Lallemand, Dominique; Vidaud, Michel; Vidaud, Dominique; Kalamarides, Michel; Parfait, Béatrice

2018-06-18

Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis. We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated. A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients. Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients.

Optical Coherence Tomography Angiography of Retinal Microvascular Changes Overlying Choroidal Nodules in Neurofibromatosis Type 1

PubMed Central

Cassiman, Catherine; Casteels, Ingele; Stalmans, Peter; Legius, Eric; Jacob, Julie

2017-01-01

Purpose To report 3 cases of neurofibromatosis type 1 (NF1) with choroidal nodules associated with retinal microvascular changes imaged with optical coherence tomography angiography (OCTA). Methods Small case series in 3 NF1 patients. OCTA examinations were performed by a trained examiner (J.J.) after pupillary dilation. A standard scan, centered over the macula measuring 6 × 6 mm and 3 × 3 mm was obtained according to the findings on standard color photography. Additional scans were obtained in the zones with microvascular abnormalities. The segmentation provided by the machine software was used. Results Corkscrew retinal vessels were observed in association with “placoid”-type choroidal nodules as shown by near-infrared reflectance imaging. In all cases, multiple lesions were found. They were second- or third-order tortuous vessels originating from the superior or inferior temporal veins. OCTA demonstrated that the tortuous venules were located in the superficial capillary plexus, and no abnormalities were found in the deep capillary plexus. Discussion Corkscrew retinal vessels are part of a spectrum of retinal microvascular alterations seen in association, sometimes overlying choroidal nodules in patients with NF1 and are visualized in the superficial capillary plexus on OCTA. We demonstrated with OCTA that they are not associated with flow loss or ischemia in the superficial and deep capillary plexus. The link between the underlying nodule remains unclear. Since neovascularization was described in choroidal ganglioneuroma, we hypothesize that corresponding secretory substances from Schwann cells, ganglion cells, or melanocytes in choroidal nodules might alter the retinal vasculature. Conclusion We report on 3 cases of NF1 with choroidal nodules in association with retinal microvascular changes imaged with OCTA. OCTA demonstrated preservation of the blood flow in the deep and superficial capillary plexus of the retina. We hypothesize that angiogenic

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.

Spinal Neurofibromatosis without Café-au-Lait Macules in Two Families with Null Mutations of the NF1 Gene

PubMed Central

Kaufmann, Dieter; Müller, Ralf; Bartelt, Britta; Wolf, Michael; Kunzi-Rapp, Karin; Hanemann, Clemens Oliver; Fahsold, Raimund; Hein, Christian; Vogel, Walther; Assum, Günter

2001-01-01

Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A→G) enlarging exon 32 by 4 bp at the 5′ end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of ∼50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency. PMID:11704931

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

Effect of Simvastatin on Cognitive Functioning in Children With Neurofibromatosis Type 1

PubMed Central

Krab, Lianne C.; de Goede-Bolder, Arja; Aarsen, Femke K.; Pluijm, Saskia M. F.; Bouman, Marlies J.; van der Geest, Jos N.; Lequin, Maarten; Catsman, Coriene E.; Arts, Willem Frans M.; Kushner, Steven A.; Silva, Alcino J.; de Zeeuw, Chris I.; Moll, Henriëtte A.; Elgersma, Ype

2009-01-01

Context Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. Objective To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention Simvastatin or placebo treatment once daily for 12 weeks. Main Outcome Measures Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. Results No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β=0.10; 95% confidence interval [CI], −0.36 to 0.56); cancellation test (β=−0.19; 95% CI, −0.67 to 0.29); prism adaptation (odds ratio=2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β=0.06; 95% CI, −0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β =0.80; 95% CI, 0.29 to 1.30). Other

Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia.

PubMed

Boudry-Labis, Elise; Roche-Lestienne, Catherine; Nibourel, Olivier; Boissel, Nicolas; Terre, Christine; Perot, Christine; Eclache, Virginie; Gachard, Nathalie; Tigaud, Isabelle; Plessis, Ghislaine; Cuccuini, Wendy; Geffroy, Sandrine; Villenet, Céline; Figeac, Martin; Leprêtre, Frederic; Renneville, Aline; Cheok, Meyling; Soulier, Jean; Dombret, Hervé; Preudhomme, Claude

2013-04-01

Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small ∼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression. Copyright © 2013 Wiley Periodicals, Inc.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 thereforemore » 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.« less

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.

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

PubMed

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

2016-11-11

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.

PedsQL Neurofibromatosis Type 1 Module for children, adolescents and young adults: feasibility, reliability, and validity.

PubMed

Nutakki, Kavitha; Varni, James W; Swigonski, Nancy L

2018-04-01

The objective of the present study was to report on the measurement properties of the Pediatric Quality of Life Inventory (PedsQL) Neurofibromatosis Type 1 Module for pediatric patients ages 5-25 from the perspectives of patients and parents. The 104-item PedsQL NF1 Module and 23-item PedsQL Generic Core Scales were completed in a multi-site national study by 323 patients and 335 parents (343 families). Patients were diagnosed with NF1 using the National Institutes of Health diagnostic criteria. In addition to a Total Scale Score, 18 unidimensional scales were derived measuring skin itch bother, skin sensations, pain, pain impact, pain management, cognitive functioning, speech, fine motor, balance, vision, perceived physical appearance, communication, worry, treatment anxiety, medicines, stomach discomfort, constipation, and diarrhea. The PedsQL NF1 Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α = 0.98; parent proxy-report α = 0.98), and good to excellent reliability for the 18 individual scales (patient self-report α = 0.71-0.96; parent proxy-report α = 0.73-0.98). Intercorrelations with the Generic Core Scales supported construct validity. Factor analysis supported the unidimensionality of the 18 individual scales. The PedsQL NF1 Module Scales demonstrated acceptable to excellent measurement properties, and may be utilized as standardized metrics to assess NF1-specific symptoms and problems in clinical research and practice in children, adolescents, and young adults.

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

PubMed

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

2017-06-01

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

Aneurysmal rupture of the costo-cervical trunk in a patient with neurofibromatosis type 1: A case report☆

PubMed Central

Hoonjan, Bhupinder; Thayur, Nagendra; Abu-Own, Abdusalam

2013-01-01

INTRODUCTION Rupture of blood vessels associated with neurofibromatosis type 1 (NF-1) is a rare but life threatening complication. We report the first case of an aneurysmal rupture from the costocervical trunk in a NF-1 patient treated by endovascular embolisation. PRESENTATION OF CASE A 43 year-old gentleman with a past medical history of NF-1 presented with sudden onset left sided neck swelling. A computed tomography (CT) revealed a large cervical haematoma, which was causing airway compromise, requiring the patient to be intubated. Percutaneous embolisation of the bleeding vessel from the costo-cervical trunk was performed with successful haemostasis and no immediate complications. A repeat CT scan showed a reduction in the original cervical haematoma. However, six days post embolisation, the patient arrested with complete whiteout of the left hemithorax. DISCUSSION CT angiography is the gold standard for diagnosis of an aneurysmal rupture in NF-1 patients, and percutaneous embolisation is the preferred modality in patients who are haemodynamically stable due to arterial fragility and high intra operative mortality rates. The increasing haemothorax could be explained by the original cervical haematoma draining down into the pleural space, or the possibility of a new second bleed. CONCLUSION This is the first reported episode of bleeding from the costocervical trunk in NF-1 patients. Ruptured aneurysms require urgent CT angiography, if haemodynamically stable, and further input from the vascular surgeons and vascular radiologists. PMID:24463561

Aneurysmal rupture of the costo-cervical trunk in a patient with neurofibromatosis type 1: A case report.

PubMed

Hoonjan, Bhupinder; Thayur, Nagendra; Abu-Own, Abdusalam

2014-01-01

Rupture of blood vessels associated with neurofibromatosis type 1 (NF-1) is a rare but life threatening complication. We report the first case of an aneurysmal rupture from the costocervical trunk in a NF-1 patient treated by endovascular embolisation. A 43 year-old gentleman with a past medical history of NF-1 presented with sudden onset left sided neck swelling. A computed tomography (CT) revealed a large cervical haematoma, which was causing airway compromise, requiring the patient to be intubated. Percutaneous embolisation of the bleeding vessel from the costo-cervical trunk was performed with successful haemostasis and no immediate complications. A repeat CT scan showed a reduction in the original cervical haematoma. However, six days post embolisation, the patient arrested with complete whiteout of the left hemithorax. CT angiography is the gold standard for diagnosis of an aneurysmal rupture in NF-1 patients, and percutaneous embolisation is the preferred modality in patients who are haemodynamically stable due to arterial fragility and high intra operative mortality rates. The increasing haemothorax could be explained by the original cervical haematoma draining down into the pleural space, or the possibility of a new second bleed. This is the first reported episode of bleeding from the costocervical trunk in NF-1 patients. Ruptured aneurysms require urgent CT angiography, if haemodynamically stable, and further input from the vascular surgeons and vascular radiologists. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phenotypic variability in monozygotic twins with neurofibromatosis 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 affectedmore » 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.« less

Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition.

PubMed

Petrella, L I; Cai, Y; Sereno, J V; Gonçalves, S I; Silva, A J; Castelo-Branco, M

2016-09-01

Neurofibromatosis type-1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain-behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1(+/-) ) using T2-weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1(+/-) mice have larger volumes than wild-type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate-putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure-function correlations were identified concerning social recognition performance and PFC volumes in Nf1(+/-) mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub-groups in Nf1(+/-) mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub-group of Nf1(+/-) mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

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. Copyright © 2011 Elsevier Inc. All rights reserved.

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

2017-03-01

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.

Development of the adult PedsQL™ neurofibromatosis type 1 module: initial feasibility, reliability and validity.

PubMed

Nutakki, Kavitha; Hingtgen, Cynthia M; Monahan, Patrick; Varni, James W; Swigonski, Nancy L

2013-02-21

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. 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. 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. 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.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1

PubMed Central

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

2017-01-01

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

Is Neurofibromatosis Type 1-Noonan Syndrome a Phenotypic Result of Combined Genetic and Epigenetic Factors?

PubMed

Yapijakis, Christos; Pachis, Nikos; Natsis, Stavros; Voumvourakis, Costas

2016-01-01

Neurofibromatosis 1-Noonan syndrome (NFNS) presents combined characteristics of both autosomal dominant disorders: NF1 and Noonan syndrome (NS). The genes causing NF1 and NS are located on different chromosomes, making it uncertain whether NFNS is a separate entity as previously suggested, or rather a clinical variation. We present a four-membered Greek family. The father was diagnosed with familial NF1 and the mother with generalized epilepsy, being under hydantoin treatment since the age of 18 years. Their two male children exhibited NFNS characteristics. The father and his sons shared R1947X mutation in the NF1 gene. The two children with NFNS phenotype presented with NF1 signs inherited from their father and fetal hydantoin syndrome-like phenotype due to exposure to that anticonvulsant during fetal development. The NFNS phenotype may be the result of both a genetic factor (mutation in the NF1 gene) and an epigenetic/environmental factor (e.g. hydantoin). Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Multivariate pattern analysis reveals subtle brain anomalies relevant to the cognitive phenotype in neurofibromatosis type 1.

PubMed

Duarte, João V; Ribeiro, Maria J; Violante, Inês R; Cunha, Gil; Silva, Eduardo; Castelo-Branco, Miguel

2014-01-01

Neurofibromatosis Type 1 (NF1) is a common genetic condition associated with cognitive dysfunction. However, the pathophysiology of the NF1 cognitive deficits is not well understood. Abnormal brain structure, including increased total brain volume, white matter (WM) and grey matter (GM) abnormalities have been reported in the NF1 brain. These previous studies employed univariate model-driven methods preventing detection of subtle and spatially distributed differences in brain anatomy. Multivariate pattern analysis allows the combination of information from multiple spatial locations yielding a discriminative power beyond that of single voxels. Here we investigated for the first time subtle anomalies in the NF1 brain, using a multivariate data-driven classification approach. We used support vector machines (SVM) to classify whole-brain GM and WM segments of structural T1 -weighted MRI scans from 39 participants with NF1 and 60 non-affected individuals, divided in children/adolescents and adults groups. We also employed voxel-based morphometry (VBM) as a univariate gold standard to study brain structural differences. SVM classifiers correctly classified 94% of cases (sensitivity 92%; specificity 96%) revealing the existence of brain structural anomalies that discriminate NF1 individuals from controls. Accordingly, VBM analysis revealed structural differences in agreement with the SVM weight maps representing the most relevant brain regions for group discrimination. These included the hippocampus, basal ganglia, thalamus, and visual cortex. This multivariate data-driven analysis thus identified subtle anomalies in brain structure in the absence of visible pathology. Our results provide further insight into the neuroanatomical correlates of known features of the cognitive phenotype of NF1. Copyright © 2012 Wiley Periodicals, Inc.

Current status and recommendations for biomarkers and biobanking in neurofibromatosis.

PubMed

Hanemann, C Oliver; Blakeley, Jaishri O; Nunes, Fabio P; Robertson, Kent; Stemmer-Rachamimov, Anat; Mautner, Victor; Kurtz, Andreas; Ferguson, Michael; Widemann, Brigitte C; Evans, D Gareth; Ferner, Rosalie; Carroll, Steven L; Korf, Bruce; Wolkenstein, Pierre; Knight, Pamela; Plotkin, Scott R

2016-08-16

Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. © 2016 American Academy of Neurology.

Current status and recommendations for biomarkers and biobanking in neurofibromatosis

PubMed Central

Blakeley, Jaishri O.; Nunes, Fabio P.; Robertson, Kent; Stemmer-Rachamimov, Anat; Mautner, Victor; Kurtz, Andreas; Ferguson, Michael; Widemann, Brigitte C.; Evans, D. Gareth; Ferner, Rosalie; Carroll, Steven L.; Korf, Bruce; Wolkenstein, Pierre; Knight, Pamela; Plotkin, Scott R.

2016-01-01

Objective: Clinically validated biomarkers for neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis (SWN) have not been identified to date. The biomarker working group's goals are to (1) define biomarker needs in NF1, NF2, and SWN; (2) summarize existing data on biomarkers in NF1, NF2, and SWN; (3) outline recommendations for sample collection and biomarker development; and (4) standardize sample collection and methodology protocols where possible to promote comparison between studies by publishing standard operating procedures (SOPs). Methods: The biomarker group reviewed published data on biomarkers in NF1, NF2, and SWN and on biobanking efforts outside these diseases via literature search, defined the need for biomarkers in NF, and developed recommendations in a series of consensus meetings. Results: We describe existing biomarkers in NF and report consensus recommendations for SOP and a minimal clinical dataset to accompany samples derived from patients with NF1, NF2, and SWN in decentralized biobanks. Conclusions: These recommendations are intended to provide clinicians and researchers with a common set of guidelines to collect and store biospecimens and for establishment of biobanks for NF1, NF2, and SWN. PMID:27527649

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

PubMed Central

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

2015-01-01

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

New type IIB backgrounds and aspects of their field theory duals

NASA Astrophysics Data System (ADS)

Caceres, Elena; Macpherson, Niall T.; Núñez, Carlos

2014-08-01

In this paper we study aspects of geometries in Type IIA and Type IIB String theory and elaborate on their field theory dual pairs. The backgrounds are associated with reductions to Type IIA of solutions with G 2 holonomy in eleven dimensions. We classify these backgrounds according to their G-structure, perform a non-Abelian T-duality on them and find new Type IIB configurations presenting dynamical SU(2)-structure. We study some aspects of the associated field theories defined by these new backgrounds. Various technical details are clearly spelled out.

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

PubMed Central

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

2014-01-01

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. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype.

PubMed

Santoro, C; Giugliano, T; Melone, M A B; Cirillo, M; Schettino, C; Bernardo, P; Cirillo, G; Perrotta, S; Piluso, G

2018-01-01

Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mid-aortic syndrome with renovascular hypertension and multisystem involvement in a girl with familiar neurofibromatosis von Recklinghausen type 1.

PubMed

Petrak, Borivoj; Bendova, Sarka; Seeman, Tomas; Klein, Tibor; Lisy, Jiri; Zatrapa, Tomas; Marikova, Tana

2007-12-01

Neurofibromatosis von Recklinghausen type 1 (NF1) is an autosomal dominant neurocutaneous disorder affecting one in 3 000-4 000 individuals. Mid-aortic syndrome (MAS) is a rare condition characterized by segmental narrowing of abdominal aorta and stenosis of its major branches - mainly renal arteries, including manifestation of renovascular hypertension. MAS can be caused by different diseases, including NF1. A 9 years old girl with primary diagnosis of NF1 combined with renovascular hypertension due to MAS, suffered of bilateral optic and chiasm glioma, pubertas praecox, speech disorder, light mental retardation and scoliosis. We have found a mutation in exone 34 of the NF1 gene (17q11.2). Her father has been also diagnosed with NF1 and hypertension developed at early age. He has the same mutation in exone 34 of NF1 gene. The girl is currently treated with conservative antihypertensive medication with positive effect. Bilateral optic and chiasm glioma are asymptomatic at the time and they had been without progress over period of time. Any vascular surgery, neurosurgical and oncological therapy are not indicated at the present time. This article is a summary of clinical findings in patient with NF1 due to NF1 gene mutation in exone 34. It confirms the importance of complex multidisciplinar approach to examination and taking care of NF1 patients and their families.

Renal artery stenting in a 2-year-old child with resistant hypertension and neurofibromatosis.

PubMed

Varghese, Kiron; Adhyapak, Srilakshmi M; Lohitashwa, S B; Pais, Priya; Iyengar, Arpana A

2017-07-01

The occurrence of vascular lesions in neurofibromatosis is uncommon but well documented. These vascular lesions when present, occur predominantly in the kidneys, endocrine glands, heart and gastrointestinal tract, causing stenosis or obliteration of the lumen. We report a case of uncontrolled resistant hypertension in a 2-year-old child presenting with neurofibromatosis who was found to have a high-grade ostial left renal artery stenosis and obliteration of the right renal artery. As the right kidney was small and hypo-functioning, and its renal artery was totally occluded, we subjected the child to a left renal angioplasty and bailout stenting. Following stenting, the blood pressure decreased with anti-hypertensive treatment. Based on a review of the literature, and to the best of our knowledge, this is the youngest child to have undergone renal artery stenting.

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

[Cerebral MRT in neurofibromatosis: gliosis versus neoplasia?].

PubMed

Mautner, V F; Pressler, M; Fünsterer, C; Schneider, E

1989-08-01

15 patients aged 1-39 years with documented neurofibromatosis had MR examinations of the cerebrum within the scope of a basic diagnosis and therapy programme. Clinical examination did not lead to pathologic findings for 7 of the patients; 3 patients suffered from general developmental disabilities. A neurologico-psychiatric examination showed pathological findings in 5 patients. Signal-intense foci in proton density and T2-weighted MR images were found in the globus pallidus, thalamus, hippocampus, cerebellum and midbrain. In 2 patients, these foci could be found as well in T1-weighted images. Differentiation between gliosis areas and low grade astrocytomas was not possible in MR.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 anmore » 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.« less

[Organization of the National Neurofibromatosis Register and areas of application].

PubMed

Horváth, András; Farkas, Viktor; Langmár, Zoltán; Bach, Rezső

2014-05-30

The neurofibromatosis is a rare genetic disease with increased tumor growing ability and different special symptoms (Riccardi-criteria). The National NF Register has been organized by NF Hungary in 2011. The idea was initiated by hungarian neurofibromatosis experts. The register contains data about the primary care physician, the hospital and the patient. The data are recorded by retrospective method and followed in time, so the register can track progress. Furthermore, the register has valid nutrition, physical activity and psychological data, so the users are able to make comparisons with the clinical information. 225 persons are registerd in the system on NF Hungary and 37 patients belong to the NF National Register. The number of patients, who are members of the registry, is always increasing. From the 37 persons 22 are females (60%) and 15 males (40%), 18 adults (48%) and 19 minors (52%). NF Register is a very useful system to do research and to draw public health and popolazione conclusions. The register enhances the morbidity details (time of manifestation, progression, prognostic factors, prognosis), thereby could improve the cooperation and the coverage of the patients. The system is open to the patients as well, so it can give them information about new scientific results, new medical treatments and currently availavable medications.

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.

Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features

PubMed Central

Goutagny, Stéphane; Bah, Alpha Boubacar; Henin, Dominique; Parfait, Béatrice; Grayeli, Alexis Bozorg; Sterkers, Olivier; Kalamarides, Michel

2012-01-01

Decision-making criteria for optimal management of meningiomas in neurofibromatosis type 2 (NF2) patients is hampered by lack of robust data, particularly long-term natural history. Seventy-four NF2 patients harboring 287 cranial meningiomas followed up for a mean period of 110.2 months were studied retrospectively. The median number of meningiomas per patient was 3. The mean maximum diameter of meningiomas at diagnosis was 14.3 mm, with a mean annual growth rate of 1.5 mm. Sixty-six percent of tumors showed no or minimal growth. In a subgroup of patients with 3D MRI, 7.3% of meningiomas (28% of patients) had a volumetric growth rate 20% or more per year. Twenty-five de novo meningiomas appeared during the follow-up (8.7%) and demonstrated a higher growth rate than other meningiomas (6.6 mm/year). Fifty-six meningiomas (23%) in 34 NF2 patients (45.9%) were operated on during the follow-up period. Among symptomatic resected meningiomas, grades II and III tumors were found in 29% and 6% of cases, respectively, with a remarkable intratumor histological heterogeneity. Single nucleotide polymorphism array analysis of 22 meningioma samples in 14 NF2 patients showed increasing chromosome instability with increasing grade, the most frequent losses being on 22q, 1p, 18q, and 6p. This study provides clues to improve tailored treatment of meningiomas: de novo and brain edema-associated meningiomas require active treatment. Future clinical trials in NF2 need to focus specifically on meningiomas as the primary endpoint and should include patients with meningiomas growing 20% or more per year in order to assess new treatments. PMID:22711605

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.

Recommendations for imaging tumor response in neurofibromatosis clinical trials

PubMed Central

Ardern-Holmes, Simone L.; Babovic-Vuksanovic, Dusica; Barker, Fred G.; Connor, Steve; Evans, D. Gareth; Fisher, Michael J.; Goutagny, Stephane; Harris, Gordon J.; Jaramillo, Diego; Karajannis, Matthias A.; Korf, Bruce R.; Mautner, Victor; Plotkin, Scott R.; Poussaint, Tina Y.; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C.

2013-01-01

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors. PMID:24249804

Recommendations for imaging tumor response in neurofibromatosis clinical trials.

PubMed

Dombi, Eva; Ardern-Holmes, Simone L; Babovic-Vuksanovic, Dusica; Barker, Fred G; Connor, Steve; Evans, D Gareth; Fisher, Michael J; Goutagny, Stephane; Harris, Gordon J; Jaramillo, Diego; Karajannis, Matthias A; Korf, Bruce R; Mautner, Victor; Plotkin, Scott R; Poussaint, Tina Y; Robertson, Kent; Shih, Chie-Schin; Widemann, Brigitte C

2013-11-19

Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

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. Copyright © 2016 AEDV. Published by Elsevier España, S.L.U. All rights reserved.

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. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: First descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes.

PubMed

Ruggieri, Martino; Praticò, Andrea D; Caltabiano, Rosario; Polizzi, Agata

2018-03-01

The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi's homuncio ("Monstrorum Historia", 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century "Buffon's Histoire Naturelle" and "Cruveilhier's Anatomie Pathologique du Corps Human". The first English language report on NF1 was made by Akenside in 1768 and the first systematic review by Robert William Smith in 1849, while Virchow's pupil, Friedrich Daniel von Recklinghausen, in 1882, was the first to understand the origin of skin tumors and to name them neurofibromas. The touching story of Joseph C. Merrick (the "Elephant man," (who had Proteus syndrome and not NF1), in 1884, played an important role in the later misconception of NF1, as did the novel by Vicotr Hugo on the hunchback Quasimodo. The studies by van der Hoeve (1921), Yakovlev and Guthrie (1931), and Van Bogaert (1935), categorized "von Recklinghausen's" neurofibromatosis among the phakomatoses and the neurocutaneous syndromes. The first known mention of an acoustic neuroma (at autopsy) is attributed to Eduard Sandifort (1777 AD) while John H. Wishart made the earliest autoptic description of neurofibromatosis type 2 (NF2), in 1822, in a 21-year-old man with bilateral acoustic neuromas, who manifested signs since his infancy (Wishart subtype NF2). Smith likely described the first case of schwannomatosis in 1849. Older, Virchow, von Recklinghausen, and Verocay first classified "neuromas" and Masson and Penfield first used the word "schwannoma" taking it from Theodore Schwann's works. In 1903 Henneberg and Koch described NF2 in detail

Safe performance of spinal anesthesia in a critical patient with neurofibromatosis, pectus carinatum, and temporomandibular joint dysfunction: A case report.

PubMed

Zencirci, Beyazit

2010-05-03

Neurofibromatosis is a syndrome caused by the abnormal deposition of neural tissues of the nervous system, endocrine system, visceral structures, and skin. On the other hand, pectus carinatum and temporomandibular joint dysfunction are illnesses that adversly affect the respiratory system and cause additional problems in airway management. Fifty-eight-year-old Turkish male patient had neurofibromatosis, pectus carinatum and temporomandibular joint dysfunction. The case was due to be operated on with the diagnosis of incarcerated umbilical hernia. Spinal anesthesia was successfully performed and the duration of the surgery was 1 hour. No postoperative complications were observed and he was discharged from the hospital on the 3rd post-operative day. The anesthetic management of patients with neurofibromatosis requires attention to all possible abnormalities and associated disturbances. Furthermore, the presence of pectus carinatum and temporomandibular joint dysfunction also increase the potential risks. The operation was successfully completed with spinal anesthesia that was carefully applied upon taking the required measures and considering all pathologies that may accompany the case and complications that may occur.

Long-term results of Gamma-knife stereotactic radiosurgery for vestibular schwannomas in patients with type 2 neurofibromatosis.

PubMed

Spatola, G; Carron, R; Delsanti, C; Thomassin, J-M; Roche, P-H; Régis, J

2016-08-12

The aim of this study was to analyze the long-term results of Gamma-knife radiosurgery treatment of vestibular schwannomas in type 2 neurofibromatosis patients. A cohort of 129 treatments for vestibular schwannomas in 103 patients was selected from a prospectively-maintained clinical database. Tumor control was assessed by volumetric analysis of the tumor at the last follow-up. Any need of a further procedure such as microsurgical removal or second treatment was regarded as a failure of tumor control. Hearing function was assessed based on Gardner-Robertson classification. Progression-free survival and functional hearing preservation rates were estimated using the Kaplan-Meier method. The median age at treatment was 34 years with no gender predominance. The median tumor volume was 1.5cm 3 . At a median clinical follow-up of 5.9 years, five patients had died, four underwent a second radiosurgical procedure and eight underwent microsurgical resection. Progression-free survival was 88 and 75% respectively at 5 and 10 years. Hearing was considered serviceable in 70 ears and remained functional in 28 ears. Kaplan-Meier estimates for 5 and 10 years functional hearing was 47 and 34%, respectively. Three patients developed new facial nerve palsy after radiosurgery at 15 days, 6 and 19 months respectively and only one partially recovered. Five patients complained of a subjective instability worsening. Four cases developed trigeminal neuropathy. No predictive factors were found to be statistically correlated with a better hearing outcome or an improved tumor growth control. Results prove less satisfying than in sporadic unilateral schwannomas. However, the lower rate of mortality and morbidity compared with microsurgical resection may support a proactive role of Gamma-knife in this pathology. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effect of higher implant density on curve correction in dystrophic thoracic scoliosis secondary to neurofibromatosis Type 1.

PubMed

Li, Yang; Yuan, Xinxin; Sha, Shifu; Liu, Zhen; Zhu, Weiguo; Qiu, Yong; Wang, Bin; Yu, Yang; Zhu, Zezhang

2017-10-01

OBJECTIVE The aim of this study was to investigate how implant density affects radiographic results and clinical outcomes in patients with dystrophic scoliosis secondary to neurofibromatosis Type 1 (NF1). METHODS A total of 41 patients with dystrophic scoliosis secondary to NF1 who underwent 1-stage posterior correction between June 2011 and December 2013 were included. General information about patients was recorded, as were preoperative and postoperative scores from Scoliosis Research Society (SRS)-22 questionnaires. Pearson correlation analysis was used to analyze the associations among implant density, coronal Cobb angle correction rate and correction loss at last follow-up, change of sagittal curve, and apical vertebral translation. Patients were then divided into 2 groups: those with low-density and those with high-density implants. Independent-sample t-tests were used to compare demographic data, radiographic findings, and clinical outcomes before surgery and at last follow-up between the groups. RESULTS Significant correlations were found between the implant density and the coronal correction rate of the main curve (r = 0.505, p < 0.01) and the coronal correction loss at final follow-up (r = -0.379, p = 0.015). There was no significant correlation between implant density and change of sagittal profile (p = 0.662) or apical vertebral translation (p = 0.062). The SRS-22 scores improved in the appearance, activity, and mental health domains within both groups, but there was no difference between the groups in any of the SRS-22 domains at final follow-up (p > 0.05 for all). CONCLUSIONS Although no significant differences between the high- and low-density groups were found in any of the SRS-22 domains at final follow-up, higher implant density was correlated with superior coronal correction and less postoperative correction loss in patients with dystrophic NF1-associated scoliosis.

Children's at Home: Pilot Study Assessing Dedicated Social Media for Parents of Adolescents with Neurofibromatosis Type 1.

PubMed

Akre, Christina; Polvinen, Julie; Ullrich, Nicole J; Rich, Michael

2018-04-01

The aim of this pilot study was to evaluate Children's at Home (C@H), a dedicated social media website for parents of adolescents with neurofibromatosis type 1 (NF1). The interventional study included two phases: (1) creating video intervention/prevention assessment (VIA) visual narratives about having an adolescent with NF1 and (2) interacting on C@H, a secure, medically moderated social media website. C@H was evaluated qualitatively at three time points. At enrollment (T0, N = 17), participants reported needing C@H to break their isolation, connect with other families, and receive accurate information, advice, and support from others facing similar challenges. At T1, after creating VIA during 6 months (N = 13, 145 videos), participants mostly valued the opportunity to speak about the challenges they face with NF1 and their journey since diagnosis. At T2, after interacting on C@H for 7 weeks (N = 10, two sign-ins/week/parent), participants reported connecting with other parents of children with NF1 for the first time, valuing the "real faces" and emotions of other parents with shared experiences providing a sense of normalcy. Qualitative analysis suggested that C@H decreased feelings of isolation, provided relief to talk about NF1 without having to explain it, provided new knowledge about NF1 and the opportunity to address non-medical issues of NF1 never discussed in clinic, and helped participants with putting their lives into perspective. C@H allowed parents of adolescents with NF1 to overcome previous isolation and connect for the first time. Innovative applications of social media dedicated to those who care for children with chronic conditions can provide peer-to-peer support, shared experience, and reliable medical information.

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. Copyright © 2012 Wiley Periodicals, Inc.

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

PubMed

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

2013-10-01

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

Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2.

PubMed

Buckley, Patrick G; Mantripragada, Kiran K; Díaz de Ståhl, Teresita; Piotrowski, Arkadiusz; Hansson, Caisa M; Kiss, Hajnalka; Vetrie, David; Ernberg, Ingemar T; Nordenskjöld, Magnus; Bolund, Lars; Sainio, Markku; Rouleau, Guy A; Niimura, Michihito; Wallace, Andrew J; Evans, D Gareth R; Grigelionis, Gintautas; Menzel, Uwe; Dumanski, Jan P

2005-12-01

Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders. Copyright 2005 Wiley-Liss, Inc.

Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.

PubMed

Widemann, Brigitte C; Babovic-Vuksanovic, Dusica; Dombi, Eva; Wolters, Pamela L; Goldman, Stewart; Martin, Staci; Goodwin, Anne; Goodspeed, Wendy; Kieran, Mark W; Cohen, Bruce; Blaney, Susan M; King, Allison; Solomon, Jeffrey; Patronas, Nicholas; Balis, Frank M; Fox, Elizabeth; Steinberg, Seth M; Packer, Roger J

2014-09-01

Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. © 2014 Wiley Periodicals, Inc.

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast-like cells.

PubMed

El-Hoss, Jad; Sullivan, Kate; Cheng, Tegan; Yu, Nicole Y C; Bobyn, Justin D; Peacock, Lauren; Mikulec, Kathy; Baldock, Paul; Alexander, Ian E; Schindeler, Aaron; Little, David G

2012-01-01

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue-specific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1(flox/flox) and Nf1(flox/-) mice. The effects of the presence of Nf1(null) cells were extensively examined. Cultured Nf1(null)-committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein-2 (rhBMP-2) treatment. Similarly, Nf1(null)-inducible osteoprogenitors obtained from Nf1 MyoDnull mouse muscle were also unresponsive to rhBMP-2. In both closed and open fracture models in Nf1(flox/flox) and Nf1(flox/-) mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1(flox/flox) and Nf1(flox/-) mice. Histological analyses showed invasion of the Nf1(null) fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10-fold in Nf1(null) fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1(null) fractures, tartrate-resistant acid phosphatase-positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable

Primary scattered multifocal melanocytomas in spinal canal mimicking neurofibromatosis.

PubMed

Yang, Chenlong; Fang, Jingyi; Li, Guang; Yang, Jun; Xu, Yulun

2016-08-01

Meningeal melanocytoma is an extremely rare pigmented tumor derived from leptomeningeal melanocytes. By and large, it is considered to be a well-differentiated and slow-growing benign lesion. Generally, meningeal melanocytomas are solitary lesions, and the occurrence of the primary multifocal form in the central nervous system is exceedingly rare; it has been previously reported in only six cases. The present report illustrates a 41-year-old woman with primary multifocal meningeal melanocytoma in the spinal canal. Contrary to earlier reports, the tumors presented with a scattered appearance mimicking neurofibromatosis. This study is a case report and review of literature. On admission, the cerebral magnetic resonance images of the patient were normal, whereas the spinal magnetic resonance images showed scattered multifocal nodules mimicking neurofibromatosis. Surgical resection of the responsible lesions was scheduled. In addition to this case presentation, relevant previous reports were reviewed, and the challenging diagnosis, management, and prognosis of meningeal melanocytoma are discussed. Gross total resection of the two largest lesions was achieved, and histopathological examinations confirmed the diagnosis. Despite the benign histopathological findings, the patient had an aggressive clinical course. On follow-up at 18 months after surgery, she succumbed to the disease. Clinicians should be alert to a potential aggressive clinical course of meningeal melanocytoma, despite its benign histopathological nature. Of particular note is multifocality and diffuse leptomeningeal hyperpigmentation, which may suggest a poor prognosis. A combined treatment including surgical resection and adjuvant radiotherapy should be considered, and long-term close follow-up is necessary. Copyright © 2016. Published by Elsevier Inc.

Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials

PubMed Central

Martin, Staci; Merker, Vanessa L.; Gardner, Kathy L.; Hingtgen, Cynthia M.; Tonsgard, James H.; Schorry, Elizabeth K.; Baldwin, Andrea

2013-01-01

Objectives: Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. Methods: The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Results: Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages ≥8 years. Conclusions: The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials. PMID:24249806

Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials.

PubMed

Wolters, Pamela L; Martin, Staci; Merker, Vanessa L; Gardner, Kathy L; Hingtgen, Cynthia M; Tonsgard, James H; Schorry, Elizabeth K; Baldwin, Andrea

2013-11-19

Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity. The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process. Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages ≥ 8 years. The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials.

The cosmic gamma-ray background from Type Ia supernovae

NASA Technical Reports Server (NTRS)

The, Lih-Sin; Leising, Mark D.; Clayton, Donald D.

1993-01-01

We present an improved calculation of the cumulative gamma-ray spectrum of Type Ia supernovae during the history of the universe. We follow Clayton & Ward (1975) in using a few Friedmann models and two simple histories of the average galaxian nucleosynthesis rate, but we improve their calculation by modeling the gamma-ray scattering in detailed numerical models of SN Ia's. The results confirm that near 1 MeV the SN Ia background may dominate, and that it is potentially observable, with high scientific importance. A very accurate measurement of the cosmic background spectrum between 0.1 and 1.0 MeV may reveal the turn-on time and the evolution of the rate of Type Ia supernova nucleosynthesis in the universe.

Human Blood Typing: A Forensic Science Approach. Part I: Background.

ERIC Educational Resources Information Center

Kobilinsky, Lawrence; Sheehan, Francis X.

1988-01-01

In this article, part I of a series, the forensic methods used in "typing" human blood, which as physical evidence is often found in the dried state, are outlined. Background information about individualization, antibody typing, fresh blood, dried blood, and additional systems is provided. (CW)

Long-term follow-up studies of Gamma Knife surgery for patients with neurofibromatosis Type 2.

PubMed

Sun, Shibin; Liu, Ali

2014-12-01

The aim of this study was to evaluate long-term clinical outcomes after Gamma Knife surgery (GKS) for patients with neurofibromatosis Type 2 (NF2) and the role of GKS in the management of NF2. From December 1994 through December 2008, a total of 46 patients (21 male, 25 female) with NF2 underwent GKS and follow-up evaluation for at least 5 years at the Gamma Knife Center of the Beijing Neurosurgical Institute. GKS was performed using the Leksell Gamma Knife Models B and C. The mean age of the patients was 30 years (range 13-59 years). A family history of NF2 was found for 9 (20%) patients. The NF2 phenotype was thought to be Wishart for 20 (44%) and Feiling-Gardner for 26 (56%) patients. Among these 46 patients, GKS was performed to treat 195 tumors (73 vestibular schwannomas and 122 other tumors including other schwannomas and meningiomas). For vestibular schwannomas, the mean volume was 5.1 cm(3) (median 3.6 cm(3), range 0.3-27.3 cm(3)), the mean margin dose was 12.9 Gy (range 10-14 Gy), and the mean maximum dose was 27.3 Gy (range 16.2-40 Gy). For other tumors, the mean volume was 1.7 cm(3) (range 0.3-5.5 cm(3)), the mean margin dose was 13.3 Gy (range 11-14 Gy), and the mean maximum dose was 26.0 Gy (range 18.0-30.4 Gy). The median duration of follow-up was 109 months (range 8-195 months). For the 73 vestibular schwannomas that underwent GKS, the latest follow-up MR images demonstrated regression of 30 (41%) tumors, stable size for 31 (43%) tumors, and enlargement of 12 (16%) tumors. The total rate of tumor control for bilateral vestibular schwannomas in patients with NF2 was 84%. Of the 122 other types of tumors that underwent GKS, 103 (85%) showed no tumor enlargement. The rate of serviceable hearing preservation after GKS was 31.9% (15/47). The actuarial rates for hearing preservation at 3 years, 5 years, 10 years, and 15 years were 98%, 93%, 44%, and 17%, respectively. Of the 46 patients, 22 (48%) became completely bilaterally deaf, 17 (37%) retained

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

Development of a practical NF1 genetic testing method through the pilot analysis of five Japanese families with neurofibromatosis type 1.

PubMed

Okumura, Akiko; Ozaki, Mamoru; Niida, Yo

2015-08-01

Mutation analysis of NF1, the responsible gene for neurofibromatosis type 1 (NF1), is still difficult due to its large size, lack of mutational hotspots, the presence of many pseudogenes, and its wide spectrum of mutations. To develop a simple and inexpensive NF1 genetic testing for clinical use, we analyzed five Japanese families with NF1 as a pilot study. Our original method, CEL endonuclease mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver staining (CHIPS) was optimized for NF1 mutation screening, and reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the effect of transcription. Also, we employed DNA microarray analysis to evaluate the break points of the large deletion. A new nonsense mutation, p.Gln209(∗), was detected in family 1 and the splicing donor site mutation, c.2850+1G>T, was detected in family 2. In family 3, c.4402A>G was detected in exon 34 and the p.Ser1468Gly missense mutation was predicted. However mRNA analysis revealed that this substitution created an aberrant splicing acceptor site, thereby causing the p.Phe1457(∗) nonsense mutation. In the other two families, type-1 and unique NF1 microdeletions were detected by DNA microarray analysis. Our results show that the combination of CHIPS and RT-PCR effectively screen and characterize NF1 point mutations, and both DNA and RNA level analysis are required to understand the nature of the NF1 mutation. Our results also suggest the possibility of a higher incidence and unique profile of NF1 large deletions in the Japanese population as compared to previous studies performed in Europe. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Multiple Café au Lait Spots in a Group of Fair-Skinned Children without Signs or Symptoms of Neurofibromatosis Type 1.

PubMed

St John, Jessica; Summe, Heather; Csikesz, Courtney; Wiss, Karen; Hay, Beverly; Belazarian, Leah

2016-09-01

The presence of six or more café au lait (CAL) spots is a criterion for the diagnosis of neurofibromatosis type 1 (NF-1). Children with multiple CAL spots are often referred to dermatologists for NF-1 screening. The objective of this case series is to characterize a subset of fair-complected children with red or blond hair and multiple feathery CAL spots who did not meet the criteria for NF-1 at the time of their last evaluation. We conducted a chart review of eight patients seen in our pediatric dermatology clinic who were previously identified as having multiple CAL spots and no other signs or symptoms of NF-1. We describe eight patients ages 2 to 9 years old with multiple, irregular CAL spots with feathery borders and no other signs or symptoms of NF-1. Most of these patients had red or blond hair and were fair complected. All patients were evaluated in our pediatric dermatology clinic, some with a geneticist. The number of CAL spots per patient ranged from 5 to 15 (mean 9.4, median 9). A subset of children, many with fair complexions and red or blond hair, has an increased number of feathery CAL spots and appears unlikely to develop NF-1, although genetic testing was not conducted. It is important to recognize the benign nature of CAL spots in these patients so that appropriate screening and follow-up recommendations may be made. © 2016 Wiley Periodicals, Inc.

Meningioangiomatosis associated with neurofibromatosis: report of 2 cases in a single family and review of the literature.

PubMed

Omeis, Ibrahim; Hillard, Virany Huynh; Braun, Alex; Benzil, Deborah L; Murali, Raj; Harter, David H

2006-06-01

Meningioangiomatosis (MA) is a rare benign disorder. It may occur sporadically or in association with neurofibromatosis (NF). The sporadic type typically presents with seizures, whereas that associated with NF is often asymptomatic. Of the 100 cases reported, only 14 are associated with NF. We now report 2 additional cases of MA associated with neurofibromatosis 2 (NF2) in a single family, with one occurring in the cerebellum. The etiology, pathology, and imaging features of MA are presented. A 38-year-old woman (patient 1) presented with a 4-month history of ataxia. She had been diagnosed previously with NF2. Magnetic resonance imaging (MRI) scans of the brain revealed bilateral acoustic neuromas and multiple calcified intracranial lesions. Her 13-year-old daughter (patient 2) presented with complex partial seizures. MRI scans of the brain revealed bilateral acoustic neuromas and a right parietal mass. Patient 1 underwent a suboccipital craniotomy to resect the right-sided acoustic neuroma. A small portion of normal-appearing cerebellar cortex was resected to avoid undue retraction. Histopathologic examination showed the presence of a lesion consistent with MA. Patient 2 underwent a right temporal-parietal craniotomy to remove the enhancing epileptogenic right posterior temporoparietal lesion. Histopathologic analysis showed a lesion consistent with meningioma and MA. MA has been reported infrequently in association with NF2. We now report 2 cases of MA associated with NF2 in one family, and we add the cerebellum to possible locations of occurrence. MA should be considered in the differential diagnosis of cortical lesions, particularly in patients with NF2.

Wounding-Induced Manifestations of Type 1 Neurofibromatosis

DTIC Science & Technology

1999-10-01

No. 86-23, Revised 1985). X For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46. SX_ In...understood how mutations at the NFl locus in specific skin cell type(s) cause these NFl skin manifestations, a role for the NF1 gene product...injures the skin and induces a wound-healing response (Scribner, 1978). Riccardi hypothesized a role for injury in pigmentation defects and tumor

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

PubMed Central

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

2011-01-01

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

Genetics Home Reference: schwannomatosis

MedlinePlus

... is usually considered to be a form of neurofibromatosis, which is a group of disorders characterized by ... nervous system. The other two recognized forms of neurofibromatosis are neurofibromatosis type 1 and neurofibromatosis type 2 . ...

Schwannomatosis: a new member of neurofibromatosis family.

PubMed

Chen, Shan-lin; Liu, Chang; Liu, Bo; Yi, Chuan-jun; Wang, Zhi-xin; Rong, Yan-bo; Zhu, Jin; Ding, Yi; Tian, Guang-lei

2013-07-01

Schwannomatosis is a recently recognized peripheral nerve polyneoplasm with clinical characteristics and a genetic background that differ from those of neurofibromatosis 2 (NF2). The diagnostic and treatment criteria of this rare disorder are herein discussed. The data of 180 patients who underwent operations for benign schwannomas from 2003 to 2012 in our center were reviewed. Eight of them were classified as schwannomatosis according to the diagnostic criteria suggested by MacCollin. The demographic characteristics were documented and compared between the two groups of patients. The patients' clinical presentations, imaging characteristics, histological features, and treatment results were retrospectively investigated and summarized. Of the 180 cases of benign schwannomas we reviewed this time, eight patients presented with schwannomatosis (4.44%). The mean age of the two groups was not significantly different (40.0 vs. 44.7 years, t = 0.88, P = 0.378). However, schwannnomatosis seems to more generally occur in females (75% vs. 48% were females, P = 0.162), although the difference was not statistically significant. The initial main symptom was pain. The neurological examination was otherwise normal. Magnetic resonance imaging (MRI) revealed multiple discrete, well-defined round, or oval lesions distributed along the course of the peripheral nerves in the extremities with low-to-intermediate signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. Vestibular schwannomas were excluded in four patients by cranial MRI. The lesions in all patients were resected and were pathologically proven to be schwannomas. The average follow-up period was 26 months. Six individuals obtained a good result without symptoms or function loss. Schwannomatosis is characterized by the development of multiple schwannomas without evidence of the vestibular tumors that are diagnostic for NF2. It commonly occurs in middle-aged females. It has similar

Isolated nonpulsatile enophthalmos in neurofibromatosis: An uncommon entity

PubMed Central

Singh, Swati; Mulay, Kaustubh; Mittal, Vikas

2017-01-01

Isolated enophthalmos is a rarely observed entity in neurofibromatosis (NF). A 12-year-old male presented with right lower eyelid fat prolapse and enophthalmos for the past 7 years. There was no history of antecedent trauma/surgery. Computed tomography of orbit revealed an ill-defined intraconal hyperdense lesion located between lateral and inferior rectus along with an enlarged inferior orbital fissure (IOF). Superior orbital fissure was minimally widened without prolapse of any intracranial contents. Excision biopsy along with repair of widened IOF was performed through inferior transconjunctival route. Histopathology was suggestive of plexiform neurofibroma with positivity for S-100 and epithelial membrane antigen. No associated cutaneous lesions were present. Nonpulsatile enophthalmos with eyelid fat prolapse can be a presenting sign of NF. PMID:29044092

Buckling Collapse of Midcervical Spine Secondary to Neurofibromatosis.

PubMed

Shah, Kunal C; Gadia, Akshay; Nagad, Premik; Bhojraj, Shekhar; Nene, Abhay

2018-06-01

Buckling collapse is the term typically used to describe severe kyphosis >100 degrees, characteristically seen in thoracolumbar tuberculosis. Neurofibromatosis is rarely associated with severe cervical kyphosis. Dystrophic changes in vertebra make surgical correction and fusion challenging. Single-stage cervical osteotomies (e.g., pedicle subtraction osteotomy, vertebral column resection) are commonly done in cervicothoracic junction. However, it is technically challenging and associated with high risk of vertebral artery injury, neural injury, etc. when performed in higher cervical spine. Hence in our case we did a staged procedure performing circumferential osteotomy for buckling kyphosis in the midcervical spine. Because it involved midcervical spine and there was no chin-to-chest deformity, we preferred the anterior-posterior-anterior sequence. Copyright © 2018 Elsevier Inc. All rights reserved.

Isolated nonpulsatile enophthalmos in neurofibromatosis: An uncommon entity.

PubMed

Singh, Swati; Mulay, Kaustubh; Mittal, Vikas

2017-10-01

Isolated enophthalmos is a rarely observed entity in neurofibromatosis (NF). A 12-year-old male presented with right lower eyelid fat prolapse and enophthalmos for the past 7 years. There was no history of antecedent trauma/surgery. Computed tomography of orbit revealed an ill-defined intraconal hyperdense lesion located between lateral and inferior rectus along with an enlarged inferior orbital fissure (IOF). Superior orbital fissure was minimally widened without prolapse of any intracranial contents. Excision biopsy along with repair of widened IOF was performed through inferior transconjunctival route. Histopathology was suggestive of plexiform neurofibroma with positivity for S-100 and epithelial membrane antigen. No associated cutaneous lesions were present. Nonpulsatile enophthalmos with eyelid fat prolapse can be a presenting sign of NF.

Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis: Impact of Family History.

PubMed

Malbari, Fatema; Spira, Menachem; B Knight, Pamela; Zhu, Chong; Roth, Michael; Gill, Jonathan; Abbott, Rick; Levy, Adam S

2018-04-20

The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1). Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported. The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029). These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.

Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study

PubMed Central

Seminog, O O; Goldacre, M J

2013-01-01

Background: The neurofibromatoses (NF) are genetic disorders. Increased risks of some cancers in people with NF are well recognised, but there is no comprehensive enumeration of the risks across the whole range of site-specific cancers. Our aim was to provide this. Methods: A linked data set of hospital admissions and deaths in England was used to compare rates of tumours in an NF cohort with rates in a comparison cohort, with results expressed as rate ratios (RR). Results: The RR for all cancers combined, in people with both types of NF combined, was 4.3 (95% confidence interval (CI): 4.0–4.6), based on 769 cases of cancer in 8003 people with NF. Considering only people with presumed NF1 (as defined in the main article), the RR for all cancers excluding nervous system malignancies remained elevated (2.7, 95% CI: 2.4–2.9); and risks were significantly high for cancer of the oesophagus (3.3), stomach (2.8), colon (2.0), liver (3.8), lung (3.0), bone (19.6), thyroid (4.9), malignant melanoma (3.6), non-Hodgkin's lymphoma (3.3), chronic myeloid leukaemia (6.7), female breast (2.3) and ovary (3.7). Conclusion: Neurofibromatosis was associated with an increased risk of many individual cancers. The relationships between NF and cancers may hold clues to mechanisms of carcinogenesis more generally. PMID:23257896

Genomic and Expression Profiling of Benign and Malignant Nerve Sheath Tumors in Neurofibromatosis Patients

DTIC Science & Technology

2008-05-01

DAMD17-03-1-0297 Title: Genomic and Expression Pr ofiling of Benign and Malignant Nerve Sheath Tumors in Neurofibromatosis Patients...have determined the gene expression signature for benign and malignant peripheral nerve sheath tumors and found that the major trend in transformation...However, EGFR data in soft tissue neoplasms is limited. Using a variety of benign and malignant spindle cell neoplasms, we assessed EGFR status by

Using a qualitative approach to conceptualize concerns of patients with neurofibromatosis type 1 associated plexiform neurofibromas (pNF) across the lifespan.

PubMed

Lai, Jin-Shei; Jensen, Sally E; Patel, Zabin S; Listernick, Robert; Charrow, Joel

2017-01-01

Neurofibromatosis Type 1 (NF1) plexiform neurofibromas (pNFs) are associated with a variety of symptoms and concerns that affect patients' quality of life (QOL), highlighting the value of incorporating the patients' perspective when evaluating treatment outcomes. To better conceptualize the experience of patients with pNFs, this qualitative study sought to identify the most important outcomes to assess from the perspective of patients, families, and clinicians. Clinicians, patients age 5 years old and above, and parents of patients aged 5-17 years participated in semi-structured interviews to elicit the pNF symptoms/concerns considered most important to assess. The data were analyzed using an iterative coding procedure and the frequency with which symptoms/concerns emerged was tabulated. Eight clinicians, 31 patients, and 17 parents of patients participated in semi-structured interviews. The most frequently reported concerns raised by patients across all age groups included pain, appearance/disfigurement, social activity/role participation, stigma, and anxiety. For parents, physical functioning was the primary concern, followed by pain, social activity/role participation, appearance/disfigurement, and social relationships. The resulting conceptual framework included five domains to represent the most important identified symptoms/concerns: pain, social functioning, physical function impact, stigma, and emotional distress. This conceptual framework describing the symptoms/concerns of patients with pNF can help investigators create a measurement system to improve assessment of aspects of QOL only patients can report on. It may also provide the ability to identify symptoms/concerns that might warrant referrals to various clinical disciplines. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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. Copyright 2001 Wiley-Liss, Inc.

On North wall in background lead type faces and storage ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

On North wall in background lead type faces and storage containers, stashed fishing gear, always kept in readiness, shop also sold fishing tackle - H. Goaziou Printshop, 807 Fallowfield Avenue, Charleroi, Washington County, PA

Mapping neurofibromatosis 1 homologous loci by fluorescence in situ hybridization

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 weremore » 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.« less

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. Copyright © 2016 AEDV. Published by Elsevier España, S.L.U. All rights reserved.

Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene.

PubMed

Thomas, Laura; Richards, Mark; Mort, Matthew; Dunlop, Elaine; Cooper, David N; Upadhyaya, Meena

2012-12-01

Neurofibromatosis type-1 (NF1) is caused by constitutional mutations of the NF1 tumor-suppressor gene. Although ∼85% of inherited NF1 microlesions constitute truncating mutations, the remaining ∼15% are missense mutations whose pathological relevance is often unclear. The GTPase-activating protein-related domain (GRD) of the NF1-encoded protein, neurofibromin, serves to define its major function as a negative regulator of the Ras-MAPK (mitogen-activated protein kinase) signaling pathway. We have established a functional assay to assess the potential pathogenicity of 15 constitutional nonsynonymous NF1 missense mutations (11 novel and 4 previously reported but not functionally characterized) identified in the NF1-GRD (p.R1204G, p.R1204W, p.R1276Q, p.L1301R, p.I1307V, p.T1324N, p.E1327G, p.Q1336R, p.E1356G, p.R1391G, p.V1398D, p.K1409E, p.P1412R, p.K1436Q, p.S1463F). Individual mutations were introduced into an NF1-GRD expression vector and activated Ras was assayed by an enzyme-linked immunosorbent assay (ELISA). Ten NF1-GRD variants were deemed to be potentially pathogenic by virtue of significantly elevated levels of activated GTP-bound Ras in comparison to wild-type NF1 protein. The remaining five NF1-GRD variants were deemed less likely to be of pathological significance as they exhibited similar levels of activated Ras to the wild-type protein. These conclusions received broad support from both bioinformatic analysis and molecular modeling and serve to improve our understanding of NF1-GRD structure and function. © 2012 Wiley Periodicals, Inc.

Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2–Associated Vestibular Schwannomas

PubMed Central

Ye, Xiaobu; Duda, Dan G.; Halpin, Chris F.; Bergner, Amanda L.; Muzikansky, Alona; Merker, Vanessa L.; Gerstner, Elizabeth R.; Fayad, Laura M.; Ahlawat, Shivani; Jacobs, Michael A.; Jain, Rakesh K.; Zalewski, Christopher; Dombi, Eva; Widemann, Brigitte C.; Plotkin, Scott R.

2016-01-01

Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell–derived factor 1α (P = .037 and .025

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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)more » 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.« less

Hilar biliary neurofibroma without neurofibromatosis: case report with contrast-enhanced ultrasound findings.

PubMed

Guo, Huan-Ling; Chen, Li-da; Wang, Zhu; Huang, Yang; Liu, Jin-Ya; Shan, Quan-Yuan; Xie, Xiao-Yan; Lu, Ming-de; Wang, Wei

2016-10-01

Solitary neurofibroma located in the hilum of the liver is extremely rare, particularly without neurofibromatosis. We herein report a case of hilar biliary neurofibroma without signs of von Recklinghausen's disease. A 36-year-old man was admitted to our department with progressive jaundice. The case was diagnosed as hilar cholangiocarcinoma based on preoperative imaging. The patient consequently received a Roux-en-Y hepaticojejunostomy and was confirmed with neurofibroma pathologically. This is the first reported imaging finding of hilar biliary neurofibroma using contrast-enhanced ultrasound, emphasizing the differential diagnosis of biliary tumors.

Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma.

PubMed Central

Wellenreuther, R.; Kraus, J. A.; Lenartz, D.; Menon, A. G.; Schramm, J.; Louis, D. N.; Ramesh, V.; Gusella, J. F.; Wiestler, O. D.; von Deimling, A.

1995-01-01

There is evidence from cytogenetic and loss of heterozygosity studies for the involvement of a tumor suppressor gene on chromosome 22 in the formation of meningiomas. Recently, the NF2 gene, which causes neurofibromatosis type 2 and which is located in the affected region on chromosome 22, has been identified. A previous study on 8 of the 17 exons of the NF2 gene described mutations in 16% of meningiomas. We have analyzed the entire coding region of the NF2 gene in 70 sporadic meningiomas and identified 43 mutations in 41 patients. These resulted predominantly in immediate truncation, splicing abnormalities, or an altered reading frame of the predicted protein product. Although there was no evidence for distinct hotspots, all mutations occurred in the first 13 exons, the region of homology with the filopodial proteins moesin, ezrin, and radixin. The association of loss of heterozygosity on chromosome 22 with mutations in the NF2 gene was significant. These data suggest that NF2 represents the meningioma locus on chromosome 22. NF2 mutations occurred significantly more frequently in fibroblastic meningioma (70%) and transitional meningioma (83%) than in meningiothelial meningioma (25%), thus indicating a differential molecular pathogenesis of these meningioma variants. Images Figure 1 PMID:7717450

Chemotherapy for the treatment of malignant peripheral nerve sheath tumors in neurofibromatosis 1: a 10-year institutional review

PubMed Central

2013-01-01

Background Neurofibromatosis 1 (NF1) is the most common autosomal dominant disorder, with an incidence of 1 in 2,500-3,300 live births. NF1 is associated with significant morbidity and mortality because of complications, especially malignant peripheral nerve sheath tumors (MPNSTs), which mainly develop during adulthood. We evaluated our experience with management of NF1 with MPNSTs by standard chemotherapy with anthracycline and/or ifosfamide in terms of time to treatment failure and overall survival. Methods We performed a retrospective review of consecutive patients with NF1 and a diagnosis of MPNSTs between 1993 and 2003 in our referral center for NF1. Prognostic factors were evaluated by univariate analysis. Results We evaluated data for 21 patients with grade 1 (n=1), grade 2 (n=8) and grade 3 (n=12) MPNST; 16 presented localized disease and underwent surgery: margins for 6 were tumor-free (including 3 patients with amputation), 2 showed microscopic residual disease and 8 showed macroscopic residual disease. All patients received chemotherapy and 9 radiotherapy. Median time to treatment failure and overall survival were 7.8 and 17 months, respectively. Two patients were still alive at 138 and 167 months. We found no significant relationship between type of chemotherapy and time to treatment failure or overall survival. Conclusions MPNSTs are highly aggressive in NF1. Conventional chemotherapy does not seem to reduce mortality, and its role must be questioned. Recent advances in the molecular biology of MPNSTs may provide new prognostic factors and targeted therapies. PMID:23972085

Malignant nerve sheath tumor involving glossopharyngeal, vagus and spinal nerve with intracranial-extracranial extension and systemic metastases in a patient with type 1 neurofibromatosis: A case report.

PubMed

Guerra-Mora, José Raúl; Del Castillo-Calcáneo, Juan D; Córdoba-Mosqueda, María Elena; Yáñez-Castro, Jorge; García-González, Ulises; Soriano-Navarro, Eduardo; Llamas-Ceras, Leticia; Vicuña-González, Rosa María

2016-01-01

Intracranial malignant peripheral nerve sheath tumors are an extremely rare pathology with a high morbidity and mortality. Epidemiological, clinical and prognostic data are scarce and with little certainty in the literature. The aim of this paper is to report for first time in English literature, the case of a patient with type 1 neurofibromatosis, who presented a malignant peripheral nerve sheath tumor that involved the left glossopharyngeal, vagus and spinal nerves with intracranial and extracranial extension through jugular foramen and systemic metastases. A 37 years-old female patient with malnutrition and Villaret́s syndrome. It was confirmed by brain magnetic resonance imaging and PET-CT the presence of a neoplasic lesion which was radiologically compatible with malignant peripheral nerve sheath tumor with systemic metastases. Partial surgical resection was performed; the patient postoperative course was without significant clinical improvement but with added peripheral facial palsy. The patient did not accept adjuvant management because of personal reasons. Behavior therapy is unclear due to the low frequency of the disease and the lack of case series, representing a challenge for the physician in its approach and a poor prognosis for the patient. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approach.

PubMed

Agrahari, Ashish Kumar; Muskan, Meghana; George Priya Doss, C; Siva, R; Zayed, Hatem

2018-05-27

The NF1 gene encodes for neurofibromin protein, which is ubiquitously expressed, but most highly in the central nervous system. Non-synonymous SNPs (nsSNPs) in the NF1 gene were found to be associated with Neurofibromatosis Type 1 disease, which is characterized by the growth of tumors along nerves in the skin, brain, and other parts of the body. In this study, we used several in silico predictions tools to analyze 16 nsSNPs in the RAS-GAP domain of neurofibromin, the K1444N (K1423N) mutation was predicted as the most pathogenic. The comparative molecular dynamic simulation (MDS; 50 ns) between the wild type and the K1444N (K1423N) mutant suggested a significant change in the electrostatic potential. In addition, the RMSD, RMSF, Rg, hydrogen bonds, and PCA analysis confirmed the loss of flexibility and increase in compactness of the mutant protein. Further, SASA analysis revealed exchange between hydrophobic and hydrophilic residues from the core of the RAS-GAP domain to the surface of the mutant domain, consistent with the secondary structure analysis that showed significant alteration in the mutant protein conformation. Our data concludes that the K1444N (K1423N) mutant lead to increasing the rigidity and compactness of the protein. This study provides evidence of the benefits of the computational tools in predicting the pathogenicity of genetic mutations and suggests the application of MDS and different in silico prediction tools for variant assessment and classification in genetic clinics.

Are the methylenetetrahydrofolate reductase 1298 and 677 gene polymorphisms related to optic glioma and hamartoma risk in neurofibromatosis type 1 patients?

PubMed

Tanyıldız, Hikmet Gülşah; Yeşil, Şule; Bozkurt, Ceyhun; Çandır, Mehmet Onur; Akpınar-Tekgündüz, Sibel; Toprak, Şule; Yüksel, Deniz; Şahin, Gürses

2016-01-01

The methylenetetrahydrofolate reductase (MTHFR) gene plays a key role in carcinogenesis through its effects on DNA synthesis and methylation and also has a significant role in the etiology of many disorders, such as diabetes, migraine, and cardiovascular disease. Neurofibromatoses (NF) are autosomal dominant inherited diseases that can affect tissues such as bone and skin and predispose individuals to tumor development in various parts of the nervous system or body. Optic nerve glioma and brain tumors are common in children with NF, and leukemia and lymphoma incidence is also higher than normal. We therefore aimed to investigate the possible relationship between the MTHFR gene polymorphism and accompanying tumors such as neurofibroma, hamartoma, and optic glioma in children with NF1 found to have the MTHFR 677 and MTHFR 1298 gene polymorphism in this study. We included 55 pediatric patients diagnosed with NF1 between 2005 and 2014 in the study group. The control group included 44 healthy subjects without acute or chronic disease findings. A significant relationship was found between the MTHFR A1298C polymorphism and the incidence of optic glioma (p=0.014) (AA vs. AC: OR 11, 95% CI 1.27-95.17; AA vs. CC: OR 7.33, 95% CI 0.35-150.70). We also found a significant relationship between the MTHFR C1298C polymorphism and the incidence of hamartoma (p=0.019) (AA vs. AC: OR 2.12, 95% CI 0.662-6.809; p=0.203). Epilepsy incidence was high in subjects with MTHFR C677C. The MTHFR A1298C, C1298C, and C677C gene polymorphisms can be associated with a higher optic glioma, hamartoma, and epilepsy incidence, respectively, in patients diagnosed with neurofibromatosis type 1.

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1.

PubMed

Evans, D Gareth R; Salvador, Hector; Chang, Vivian Y; Erez, Ayelet; Voss, Stephan D; Schneider, Kami Wolfe; Scott, Hamish S; Plon, Sharon E; Tabori, Uri

2017-06-15

Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46-e53. ©2017 AACR See all articles in the online-only CCR Pediatric Oncology Series . ©2017 American Association for Cancer Research.

Patient-reported outcomes of pain and physical functioning in neurofibromatosis clinical trials.

PubMed

Wolters, Pamela L; Martin, Staci; Merker, Vanessa L; Tonsgard, James H; Solomon, Sondra E; Baldwin, Andrea; Bergner, Amanda L; Walsh, Karin; Thompson, Heather L; Gardner, Kathy L; Hingtgen, Cynthia M; Schorry, Elizabeth; Dudley, William N; Franklin, Barbara

2016-08-16

Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials. The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials. The REiNS PRO group chose the Numeric Rating Scale-11 (≥8 years) to assess pain intensity, the Pain Interference Index (6-24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (≥18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (≥5 years) for NF clinical trials. The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research. © 2016 American Academy of Neurology.

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. © 2015 Wiley Periodicals, Inc.

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

Osteoclasts in neurofibromatosis type 1 display enhanced resorption capacity, aberrant morphology, and resistance to serum deprivation.

PubMed

Heervä, Eetu; Alanne, Maria H; Peltonen, Sirkku; Kuorilehto, Tommi; Hentunen, Teuvo; Väänänen, Kalervo; Peltonen, Juha

2010-09-01

Neurofibromatosis 1 syndrome (NF1) presents with skeletal involvement suggesting that altered bone dynamics is associated with NF1. Histological analysis of three cases of NF1-related pseudarthrosis revealed numerous osteoclasts in contact with adjacent bone, and within the pseudarthrosis tissue itself. These findings prompted us to evaluate the differentiation and resorption capacity of NF1-osteoclast like cells (OLCs) in vitro. Osteoclast progenitors were isolated from peripheral blood of 17 patients with NF1 and allowed to differentiate into OLCs on bone slices. The following differences were found between NF1 and control samples: samples from NF1 patients resulted in a higher number of resorbing OLCs; NF1 OLCs were larger in size; their nuclei were more numerous; actin rings were more frequent; and the resorption pits in NF1 samples were more numerous and larger. Bone resorption markers revealed that the resorption activity in NF1 OLC cultures was approximately two times higher than in controls. Following deprivation from serum, the number of NF1 OLCs remained essentially the same during 24h, whereas the number of control OLCs was dramatically reduced during the same time. Three patients had NF1-related lytic bone lesions, and their in vitro results differed from those of other patients. Our results demonstrate that OLCs derived from blood of patients with NF1 display elevated resorption activity under conditions isolated from microenvironment operative in vivo. Thus, increased osteoclast activity may be a phenotypic property of the NF1 syndrome, and at least in part explain selected skeletal findings in NF1, such as osteoporosis/osteopenia. Copyright 2010 Elsevier Inc. All rights reserved.

The course of cognitive-behavioral development in children with the FMR1 mutation, Williams-Beuren syndrome, and neurofibromatosis type 1: The effect of gender.

PubMed

Fisch, Gene S; Carpenter, Nancy; Howard-Peebles, Patricia N; Holden, Jeanette J A; Tarleton, Jack; Simensen, Richard

2010-06-01

The course of cognitive-behavioral development in children with intellectual disabilities produced by genetic disorders has only recently begun to be examined systematically. Unfortunately, these studies are few in number. Previously, we examined cognitive-behavioral development in children with the fragile X (FMR1) mutation and found longitudinal decreases in both IQ and adaptive behavior (DQ) scores in most males and females with the full mutation. In this study, we examine longitudinal changes in IQ and DQ in children with neurofibromatosis type 1 (NF1) and Williams-Beuren Syndrome (WBS) by examining differences in composite IQ and DQ scores between the first test (T1) and retest (T2), and compare their developmental trajectory to children with the FMR1 mutation. Sixty-five children with the FMR1 mutation, or NF1, or WBS, ages 4-16 years, were retested two years after initial testing with the Stanford-Binet 4th Edition (SBFE) and the Vineland Adaptive Behavior Scale (VABS). In addition to significant longitudinal declines in IQ and DQ noted previously in children with the FMR1 mutation, we found significant decreases in IQ in males compared to females in the remainder of our sample. We also observed statistically significant decreases in DQ scores among children the FMR1 mutation, as noted previously, but not among children with NF1 or WBS. Moreover, significant declines were found only among males with the FMR1 mutation. Unlike declines in IQ scores, decreases in DQ were not significantly different between males and females. (c) 2010 Wiley-Liss, Inc.

Posterior-only surgical correction of dystrophic scoliosis in 31 patients with neurofibromatosis Type 1 using the multiple anchor point method.

PubMed

Deng, Ang; Zhang, Hong-Qi; Tang, Ming-Xing; Liu, Shao-Hua; Wang, Yu-Xiang; Gao, Qi-Le

2017-01-01

OBJECTIVE The objective of this study was to evaluate the clinical efficacy of posterior-only surgical correction of dystrophic scoliosis in patients with neurofibromatosis Type 1 (NF1) using a multiple anchor point method (MAPM). METHODS From 2005 to 2014, 31 patients (mean age 13.5 years old, range 10-22 years old) suffering from dystrophic scoliosis associated with NF1 underwent posterior-only surgical correction using a MAPM. The apex of the deformity was thoracic (n = 25), thoracolumbar (n = 4), and lumbar (n = 2). The mean preoperative coronal Cobb angle was 69.1° (range 48.9°-91.4°). The mean Cobb angle on the side-bending radiograph of the convex side was 58.2° (range 40°-79.8°). The mean flexibility and apical vertebral rotation (AVR) were 15.6% (range 8.3%-28.2%) and 2.5° (range 2°-3°), respectively. The mean angle of sagittal kyphosis was 58.3° (range 34.1°-79.6°). RESULTS The mean follow-up period was 53 months (range 12-96 months). The mean postoperative coronal Cobb angle was 27.4° (range 16.3°-46.7°). Postoperatively, the mean AVR and angle of sagittal kyphosis were 1.2° (range 1°-2°) and 22.4° (range 4.2°-36.3°), respectively. All patients showed good correction of all indices postoperatively. The mean postoperative correction rate was 58.7% (range 46.3%-74.1%). At the final follow-up evaluation, the corrective loss rate of the Cobb angle was only 2.3%. Only 1 patient required revision surgery. No severe complications such as spinal cord, neural, or large vascular injury occurred during the operation. CONCLUSIONS Posterior-only surgical correction of dystrophic scoliosis in patients with NF1 using a MAPM could yield satisfactory clinical efficacy of correction and fusion.

Contributions of late-type dwarf stars to the soft X-ray diffuse background

NASA Technical Reports Server (NTRS)

Schmitt, J. H. M. M.; Snowden, S. L.

1990-01-01

Comprehensive calculations of the contribution of late-type dwarf stars to the soft X-ray diffuse background are presented. The mean X-ray luminosity as derived from optically and X-ray selected samples is examined, using the Bahcall-Soneira Galaxy model to describe the spatial distribution of stars and recent results on the X-ray spectra. The model calculations are compared with the Wisconsin sky maps in the C, M1, M2, I and J bands to assess the uncertainties of the calculations. Contributions of up to 10 percent to the M2 and I band background at high Galactic latitudes are found, while at low Galactic latitudes late-type stars contribute up to 40 percent of the background. However, a Galactic ridge as well as a relatively isotropic component still remains unexplained, even with the added contribution of the extrapolated high-energy power law.

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

DTIC Science & Technology

2014-05-01

identify modulators of this important disease. 15. SUBJECT TERMS Neurofibromatosis ; learning and memory; glioma; MPNST 16. SECURITY CLASSIFICATION...12-13 Page 3 INTRODUCTION Neurofibromatosis type 1...result indicates that sox10 is highly expressed in high-grade gliomas and MPNSTs in our zebrafish model of type I neurofibromatosis . Figure 4. Sox10

Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis.

PubMed

Plotkin, Scott R; Bredella, Miriam A; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J; Esparza, Sonia; Merker, Vanessa L; Munn, Lance L; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F

2012-01-01

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations.

Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

PubMed Central

Plotkin, Scott R.; Bredella, Miriam A.; Cai, Wenli; Kassarjian, Ara; Harris, Gordon J.; Esparza, Sonia; Merker, Vanessa L.; Munn, Lance L.; Muzikansky, Alona; Askenazi, Manor; Nguyen, Rosa; Wenzel, Ralph; Mautner, Victor F.

2012-01-01

Purpose Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease. Methods We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors. Results WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10). Conclusion WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations. PMID:22558206

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). © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Social Network, Socioeconomic Background, and School Type of Adolescent Smokers

ERIC Educational Resources Information Center

Huisman, Chip; Bruggeman, Jeroen

2012-01-01

The aim of this study is to examine the role of Dutch second grade (age 13-14) high school peer networks in mediating socioeconomic background and school type effects on smoking behavior. This study is based on a longitudinal design with two measurement waves at five different high schools, of the complete networks of second grader friendships, as…

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.

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.

The relationship between patients' perception of the effects of neurofibromatosis type 2 and the domains of the Short Form-36.

PubMed

Neary, W J; Hillier, V F; Flute, T; Stephens, S D G; Ramsden, R T; Evans, D G R

2010-08-01

To investigate the relationship between those issues concerning quality of life in patients with neurofibromatosis type 2 (NF2) as identified by the closed set NF2 questionnaire and the eight norm-based measures and the physical component summary (PCS) and mental component summary (MCS) scores of the Short Form-36 (SF-36) Questionnaire. Postal questionnaire study. Questionnaires sent to subjects' home addresses. Eighty-seven adult subjects under the care of the Manchester Multidisciplinary NF2 Clinic were invited to participate. Sixty-two (71%) completed sets of closed set NF2 questionnaires and SF-36 questionnaires were returned. Subjects with NF2 scored less than the norm of 50 on both the physical component summary and mental component summary scores and the eight individual norm-based measures of the Short Form-36 questionnaire. Correlations (using Kendall's tau) were examined between patients' perceptions of their severity of difficulty with the following activities and the eight norm-based measures and the physical component summary and mental component summary scores of the Short Form-36 questionnaire: Communicating with spouse/significant other (N = 61). The correlation coefficients were significant at the 0.01 level for the mental component summary score, together with three of the norm-based scores [vitality (VT), social functioning and role emotional]. Social communication (N = 62). All 10 correlations were significant at the 0.01 or 0.001 level. Balance (N = 59). All 10 correlations were highly significant at the P < 0.001 level. Hearing difficulties (N = 61). All correlations were significant at either the 0.01 level or less apart from the mental component summary score and three of the norm-based scores (role physical, VT and mental health). Mood change (N = 61). All correlations were significant at the 0.01 level or less, apart from one norm-based score (role physical). The Short Form-36 questionnaire has allowed us to relate patients' perceptions of

Examination of the mGluR-mTOR Pathway for the Identification of Potential Therapeutic Targets to Treat Fragile X

DTIC Science & Technology

2014-10-01

of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Rep. 2014 Sep 11;8(5...that are already present in childhood as was first demonstrated in animal models of Fragile X and Neurofibromatosis type 1 in 2005 (Li et al., 2005...learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 15:1961-1967. Liu ZH, Chuang DM, Smith CB (2011) Lithium

Engineered Herpes Simplex Viruses for the Treatment of Malignant Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2014-09-01

patients with neurofibromatosis type I (NF-1) will develop benign neurofibromas in their peripheral nerves that will progress to malignant tumors that...lines to activate anti-viral signaling pathways. Keywords: MPNST, neurofibromatosis , oncolytic virus, HSV-1, IL-12 In the first year of research, we...lysis and immune recruitment. As rare and aggressive tumors of glial origin, MPNSTs frequently arise from patients with type-1 neurofibromatosis , but

Influence of background noise on the performance in the odor sensitivity task: effects of noise type and extraversion.

PubMed

Seo, Han-Seok; Hähner, Antje; Gudziol, Volker; Scheibe, Mandy; Hummel, Thomas

2012-10-01

Recent research demonstrated that background noise relative to silence impaired subjects' performance in a cognitively driven odor discrimination test. The current study aimed to investigate whether the background noise can also modulate performance in an odor sensitivity task that is less cognitively loaded. Previous studies have shown that the effect of background noise on task performance can be different in relation to degree of extraversion and/or type of noise. Accordingly, we wanted to examine whether the influence of background noise on the odor sensitivity task can be altered as a function of the type of background noise (i.e., nonverbal vs. verbal noise) and the degree of extraversion (i.e., introvert vs. extrovert group). Subjects were asked to conduct an odor sensitivity task in the presence of either nonverbal noise (e.g., party sound) or verbal noise (e.g., audio book), or silence. Overall, the subjects' mean performance in the odor sensitivity task was not significantly different across three auditory conditions. However, with regard to the odor sensitivity task, a significant interaction emerged between the type of background noise and the degree of extraversion. Specifically, verbal noise relative to silence significantly impaired or improved the performance of the odor sensitivity task in the introvert or extrovert group, respectively; the differential effect of introversion/extraversion was not observed in the nonverbal noise-induced task performance. In conclusion, our findings provide new empirical evidence that type of background noise and degree of extraversion play an important role in modulating the effect of background noise on subjects' performance in an odor sensitivity task.

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

Mutational analysis of patients with neurofibromatosis 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacCollin, M.; Ramesh, V.; Pulaski, K.

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 leastmore » 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.« less

Optic glioma

MedlinePlus

... is a strong association between optic glioma and neurofibromatosis type 1 ( NF1 ). Symptoms The symptoms are due ... brain (intracranial pressure). There may be signs of neurofibromatosis type 1 (NF1). The following tests may be ...

The Role of NF1 in Memory Retrieval

DTIC Science & Technology

2014-09-01

ABSTRACT This
three‐year
grant
supports
our
efforts
in
studying
a
role
of
the
 neurofibromatosis 
type
 1
(NF1)
gene
in
mediating
retrieval
of
long‐term...year extension. The proposed research investigates involvement of neurofibromatosis type 1 gene-encoded neurofibromin (NF1) in retrieval of long...mutations of this gene lead to the most common monogenic disorder, neurofibromatosis type 1. The critical role of NF1 in learning and memory has been

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

PubMed

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

2016-06-01

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

Effect of coping thickness and background type on the masking ability of a zirconia ceramic.

PubMed

Tabatabaian, Farhad; Taghizade, Fateme; Namdari, Mahshid

2018-01-01

The masking ability of zirconia ceramics as copings is unclear. The purpose of this in vitro study was to evaluate the effect of coping thickness and background type on the masking ability of a zirconia ceramic and to determine zirconia coping thickness cut offs for masking the backgrounds investigated. Thirty zirconia disks in 3 thickness groups of 0.4, 0.6, and 0.8 mm were placed on 9 backgrounds to measure CIELab color attributes using a spectrophotometer. The backgrounds included A1, A2, and A3.5 shade composite resin, A3 shade zirconia, nickel-chromium alloy, nonprecious gold-colored alloy, amalgam, black, and white. ΔE values were measured to determine color differences between the specimens on the A2 shade composite resin background and the same specimens on the other backgrounds. The color change (ΔE) values were compared with threshold values for acceptability (ΔE=5.5) and perceptibility (ΔE=2.6). Repeated measures ANOVA, the Bonferroni test, and 1-sample t tests were used to analyze data (α=.05). Mean ΔE values ranged between 1.44 and 7.88. The zirconia coping thickness, the background type, and their interaction affected the CIELab and ΔE values (P<.001). To achieve ideal masking, the minimum thickness of a zirconia coping should be 0.4 mm for A1 and A3.5 shade composite resin, A3 shade zirconia, and nonprecious gold-colored alloy, 0.6 mm for amalgam, and 0.8 mm for nickel-chromium alloy. Copyright © 2017 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

Is magnetic resonance spectroscopy capable of detecting metabolic abnormalities in neurofibromatosis type 1 that are not revealed in brain parenchyma of normal appearance?

PubMed

Rodrigues, Antonio Carlos Pondé; Ferraz-Filho, José Roberto Lopes; Torres, Ulysses S; da Rocha, Antônio José; Muniz, Marcos Pontes; Souza, Antônio Soares; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

2015-03-01

Results of magnetic resonance spectroscopy studies in normal-appearing brain and in non-neoplastic brain lesions in individuals with neurofibromatosis type 1 (NF1) have been discrepant. We used magnetic resonance spectroscopy to analyze the metabolic patterns in the basal ganglia of patients with NF1 and examine their correlation with focal hyperintense lesions in T2-weighted images (T2-weighted hyperintensities). We used magnetic resonance spectroscopy data of 42 individuals with NF1 (18 with and 24 without T2- weighted hyperintensities) and 25 controls matched for gender and age. A single-voxel technique was employed by manually placing a region of interest with a uniform size over a predetermined anatomical region including the globus pallidum and putamen (capsulolenticular region). We further analyzed the ratios of choline/creatine, N-acetyl aspartate (NAA)/creatine, and myoinositol/creatine metabolites and the occurrence of T2-weighted hyperintensities in these regions in individuals with NF1. There was a significant difference between the NF1 and control groups with regard to the mean values of myoinositol/creatine and choline/creatine, with higher metabolite values observed in the NF1 group (P < 0.001). Only the myoinositol/creatine ratio was able to discriminate between NF1 subgroups with and without T2-weighted hyperintensities. For the NAA/creatine ratio, there was no significant difference between the NF1 and the control groups. Magnetic resonance spectroscopy allows the characterization of tissue abnormalities not demonstrable in the structural images of individuals with NF1 through choline and myoinositol metabolite analysis. Yet the preserved NAA values argue against demyelination and axonal degeneration occurring in the region, suggesting instead a functional neuronal stability. Taken in association with the findings of lack of clinical manifestations and the known transient nature of T2-weighted hyperintensities in NF1 as demonstrated by other

Genetic analysis of eight loci tightly linked to neurofibromatosis 1

PubMed Central

Stephens, Karen; Green, Philip; Riccardi, Vincent M.; Ng, Siu; Rising, Marcia; Barker, David; Darby, John K.; Falls, Kathleen M.; Collins, Francis S.; Willard, Huntington F.; Donis-Keller, Helen

1989-01-01

The genetic locus for neurofibromatosis 1 (NF1) has recently been mapped to the pericentromeric region of chromosome 17. We have genotyped eight previously identified RFLP probes on 50 NF1 families to determine the placement of the NF1 locus relative to the RFLP loci. Thirty-eight recombination events in the pericentromeric region were identified, eight involving crossovers between NF1 and loci on either chromosomal arm. Multipoint linkage analysis resulted in the unique placement of six loci at odds >100:1 in the order of pter–A10-41–EW301–NF1–EW207–CRI-L581–CRI-L946–qter. Owing to insufficient crossovers, three loci–D17Z1, EW206, and EW203–could not be uniquely localized. In this region female recombination rates were significantly higher than those of males. These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome 17. PMID:2491775

The Diffuse Gamma-Ray Background from Type Ia Supernovae

NASA Technical Reports Server (NTRS)

Lien, Amy; Fields, Brian D.

2012-01-01

The origin of the diffuse extragalactic gamma-ray background (EGB) has been intensively studied but remains unsettled. Current popular source candidates include unresolved star-forming galaxies, starburst galaxies, and blazars. In this paper we calculate the EGB contribution from the interactions of cosmic rays accelerated by Type Ia supernovae, extending earlier work which only included core-collapse supernovae. We consider Type Ia events in star-forming galaxies, but also in quiescent galaxies that lack star formation. In the case of star-forming galaxies, consistently including Type Ia events makes little change to the star-forming EGB prediction, so long as both supernova types have the same cosmic-ray acceleration efficiencies in star-forming galaxies. Thus our updated EGB estimate continues to show that star-forming galaxies can represent a substantial portion of the signal measured by Fermi. In the case of quiescent galaxies, conversely, we find a wide range of possibilities for the EGB contribution. The dominant uncertainty we investigated comes from the mass in hot gas in these objects, which provides targets for cosmic rays: total gas masses are as yet poorly known, particularly at larger radii. Additionally, the EGB estimation is very sensitive to the cosmic-ray acceleration efficiency and confinement, especially in quiescent galaxies. In the most optimistic allowed scenarios, quiescent galaxies can be an important source of the EGB. In this case, star-forming galaxies and quiescent galaxies together will dominate the EGB and leave little room for other contributions. If other sources, such as blazars, are found to have important contributions to the EGB, then either the gas mass or cosmic-ray content of quiescent galaxies must be significantly lower than in their star-forming counterparts. In any case, improved Fermi EGB measurements will provide important constraints on hot gas and cosmic rays in quiescent galaxies.

Oral Ketamine in the Palliative Care Setting: A Review of the Literature and Case Report of a Patient With Neurofibromatosis Type 1 and Glomus Tumor-Associated Complex Regional Pain Syndrome

PubMed Central

Soto, Eliezer; Stewart, Douglas R.; Mannes, Andrew J.; Ruppert, Sarah L.; Baker, Karen; Zlott, Daniel; Handel, Daniel; Berger, Ann M.

2014-01-01

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective not only for its anesthetic properties but also for the analgesic and opiate-sparing effects. However, data on efficacy and safety of oral ketamine for the treatment of neuropathic or cancer pain syndromes is limited with most of the evidence based on small clinical trials and anecdotal experiences. In this review, we will analyze the clinical data on oral ketamine in the palliative care setting. After an extensive search using five major databases, a total of 19 relevant articles were included. No official clinical guidelines for the use of oral ketamine in this patient population were found. Studies on oral ketamine for cancer and neuropathic pain have shown mixed results which could be partially due to significant differences in hepatic metabolism. In addition, we will include a case report of a 38-year-old female with neurofibromatosis type 1 (NF1) with history of chronic, severe pain in her fingertips secondary to multiple glomus tumors which evolved into CRPS resistant to multiple therapies but responsive to oral ketamine. Based on our experience with oral ketamine, this drug should be administered after an intravenous trial to monitor response and side effects in patients with an adequate functional status. However, patients in the palliative care and hospice setting, especially the one at the end of their lives, may also benefit from oral ketamine even if an intravenous trial is not feasible. PMID:21803784

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. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-06-15

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

Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors

DTIC Science & Technology

2014-04-01

Neurofibromatosis type 2 tumor suppressor protein, merlin, by adhesion and growth arrest stimuli. J Biol Chem 273: 7757-64. 25. Shaw, R.J...McClatchey, A.I., and Jacks, T. (1998) Localization and functional domains of the Neurofibromatosis type II tumor suppressor, merlin. Cell Growth Diff 9

Whole Body MRI at 3T with Quantitative Diffusion Weighted Imaging and Contrast-Enhanced Sequences for the Characterization of Peripheral Lesions in Patients with Neurofibromatosis Type 2 and Schwannomatosis.

PubMed

Fayad, Laura M; Blakeley, Jaishri; Plotkin, Scott; Widemann, Brigitte; Jacobs, Michael A

2013-01-01

Purpose. WB-MRI is mainly used for tumor detection and surveillance. The purpose of this study is to establish the feasibility of WB-MRI at 3T for lesion characterization, with DWI/ADC-mapping and contrast-enhanced sequences, in patients with neurofibromatosis type 2 (NF-2) and schwannomatosis. Materials and Methods. At 3T, WB-MRI was performed in 11 subjects (10 NF-2 and 1 schwannomatosis) with STIR, T1, contrast-enhanced T1, and DWI/ADC mapping (b = 50, 400, 800 s/mm(2)). Two readers reviewed imaging for the presence and character of peripheral lesions. Lesion size and features (signal intensity, heterogeneity, enhancement characteristics, and ADC values) were recorded. Descriptive statistics were reported. Results. Twenty-three lesions were identified, with average size of 4.6 ± 2.8 cm. Lesions were characterized as tumors (21/23) or cysts (2/23) by contrast-enhancement properties (enhancement in tumors, no enhancement in cysts). On T1, tumors were homogeneously isointense (5/21) or hypointense (16/21); on STIR, tumors were hyperintense and homogeneous (10/21) or heterogeneous (11/21); on postcontrast T1, tumors enhanced homogeneously (14/21) or heterogeneously (7/21); on DWI, tumor ADC values were variable (range 0.8-2.7), suggesting variability in intrinsic tumor properties. Conclusion. WB-MRI with quantitative DWI and contrast-enhanced sequences at 3T is feasible and advances the utility of WB-MRI not only to include detection, but also to provide additional metrics for lesion characterization.

Whole Body MRI at 3T with Quantitative Diffusion Weighted Imaging and Contrast-Enhanced Sequences for the Characterization of Peripheral Lesions in Patients with Neurofibromatosis Type 2 and Schwannomatosis

PubMed Central

Fayad, Laura M.; Blakeley, Jaishri; Plotkin, Scott; Widemann, Brigitte; Jacobs, Michael A.

2013-01-01

Purpose. WB-MRI is mainly used for tumor detection and surveillance. The purpose of this study is to establish the feasibility of WB-MRI at 3T for lesion characterization, with DWI/ADC-mapping and contrast-enhanced sequences, in patients with neurofibromatosis type 2 (NF-2) and schwannomatosis. Materials and Methods. At 3T, WB-MRI was performed in 11 subjects (10 NF-2 and 1 schwannomatosis) with STIR, T1, contrast-enhanced T1, and DWI/ADC mapping (b = 50, 400, 800 s/mm2). Two readers reviewed imaging for the presence and character of peripheral lesions. Lesion size and features (signal intensity, heterogeneity, enhancement characteristics, and ADC values) were recorded. Descriptive statistics were reported. Results. Twenty-three lesions were identified, with average size of 4.6 ± 2.8 cm. Lesions were characterized as tumors (21/23) or cysts (2/23) by contrast-enhancement properties (enhancement in tumors, no enhancement in cysts). On T1, tumors were homogeneously isointense (5/21) or hypointense (16/21); on STIR, tumors were hyperintense and homogeneous (10/21) or heterogeneous (11/21); on postcontrast T1, tumors enhanced homogeneously (14/21) or heterogeneously (7/21); on DWI, tumor ADC values were variable (range 0.8–2.7), suggesting variability in intrinsic tumor properties. Conclusion. WB-MRI with quantitative DWI and contrast-enhanced sequences at 3T is feasible and advances the utility of WB-MRI not only to include detection, but also to provide additional metrics for lesion characterization. PMID:24967287

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

PubMed

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

2017-01-01

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

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

DTIC Science & Technology

2015-04-01

Patients with Neurofibromatosis type 1 (NF1) are at increased risk for developing malignant tumors of the connective tissue called soft-tissue sarcomas...mouse model, MPNST, Neurofibromatosis , NF1 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE...9 9. Appendices……………………………………………………………9 4   1. INTRODUCTION: Patients with Neurofibromatosis type 1 (NF1) are at increased risk for

Neurofibromatosis 1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like symptoms

PubMed Central

Waheed, Waqar; Nathan, Muriel H; Allen, Gilman B; Borden, Neil M; Babi, M Ali; Tandan, Rup

2015-01-01

A 37-year-old man with a known history of neurofibromatosis 1 (NF1) presented within 2 days of diarrhoeal illness followed by encephalopathy, facial twitching, hypoglycaemia, hypotension, tachycardia and low-grade fever. Examination showed multiple café-au-lait spots and neurofibromas over the trunk, arms and legs and receptive aphasia with right homonymous hemianopia, which resolved. Workup for cardiac, inflammatory and infectious aetiologies was unrevealing. A brain MRI showed gyral swelling with increased T2 fluid-attenuated inversion recovery signal and diffusion restriction in the left cerebral cortex. Neuroendocrine findings suggested panhypopituitarism with centrally derived adrenal insufficiency. Supportive treatment, hormone supplementation, antibiotics, antivirals and levetiracetam yielded clinical improvement. A follow-up brain MRI showed focal left parieto-occipital atrophy with findings of cortical laminar necrosis. In conclusion, we describe a case of NF1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like findings, hitherto unreported manifestations of NF1. Prompt recognition and treatment of these associated conditions can prevent devastating complications. PMID:26531733

Novel Role of Merlin Tumor Suppressor in Autophagy and Its Implication in Treating NF2-Associated Tumors

DTIC Science & Technology

2015-06-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the... Neurofibromatosis  type 2 (NF2) is an autosomal dominant disorder characterized by the development of  brain tumors of peripheral nervous system origin...in autophagy and tumorigenesis, and will to  contribute to the development of new therapies means against NF2.    Key words:  Neurofibromatosis  type 2

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. © 2014 Wiley Periodicals, Inc.

Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

DTIC Science & Technology

2014-06-01

approximately 90% of patients with neurofibromatosis , are associated with cognitive impairment. Impaired academic performance is common and often requires...associated with neurofibromatosis is hard to study in humans. The phenotypes observed in mice indicate a specific function for Neurofibromin in the...year of the project. References 1 Acosta, M. T., Gioia, G. A. & Silva, A. J. Neurofibromatosis type 1: new insights into neurocognitive issues

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

PubMed Central

Stowe, Irma B.; Mercado, Ellen L.; Stowe, Timothy R.; Bell, Erika L.; Oses-Prieto, Juan A.; Hernández, Hilda; Burlingame, Alma L.; McCormick, Frank

2012-01-01

The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome. PMID:22751498

Pedicle screw versus hybrid posterior instrumentation for dystrophic neurofibromatosis scoliosis.

PubMed

Wang, Jr-Yi; Lai, Po-Liang; Chen, Wen-Jer; Niu, Chi-Chien; Tsai, Tsung-Ting; Chen, Lih-Huei

2017-06-01

Surgical management of severe rigid dystrophic neurofibromatosis (NF) scoliosis is technically demanding and produces varying results. In the current study, we reviewed 9 patients who were treated with combined anterior and posterior fusion using different types of instrumentation (i.e., pedicle screw, hybrid, and all-hook constructs) at our institute.Between September 2001 and July 2010 at our institute, 9 patients received anterior release/fusion and posterior fusion with different types of instrumentation, including a pedicle screw construct (n = 5), a hybrid construct (n = 3), and an all-hook construct (n = 1). We compared the pedicle screw group with the hybrid group to analyze differences in preoperative curve angle, immediate postoperative curve reduction, and latest follow-up curve angle.The mean follow-up period was 9.5 ± 2.9 years. The average age at surgery was 10.3 ± 3.9 years. The average preoperative scoliosis curve was 61.3 ± 13.8°, and the average preoperative kyphosis curve was 39.8 ± 19.7°. The average postoperative scoliosis and kyphosis curves were 29.7 ± 10.7° and 21.0 ± 13.5°, respectively. The most recent follow-up scoliosis and kyphosis curves were 43.4 ± 17.3° and 29.4 ± 18.9°, respectively. There was no significant difference in the correction angle (either coronal or sagittal), and there was no significant difference in the loss of sagittal correction between the pedicle screw construct group and the hybrid construct group. However, the patients who received pedicle screw constructs had significantly less loss of coronal correction (P < .05). Two patients with posterior instrumentation, one with an all-hook construct and the other with a hybrid construct, required surgical revision because of progression of deformity.It is difficult to intraoperatively correct dystrophic deformity and to maintain this correction after surgery. Combined anterior release/fusion and posterior

Pedicle screw versus hybrid posterior instrumentation for dystrophic neurofibromatosis scoliosis

PubMed Central

Wang, Jr-Yi; Lai, Po-Liang; Chen, Wen-Jer; Niu, Chi-Chien; Tsai, Tsung-Ting; Chen, Lih-Huei

2017-01-01

Abstract Surgical management of severe rigid dystrophic neurofibromatosis (NF) scoliosis is technically demanding and produces varying results. In the current study, we reviewed 9 patients who were treated with combined anterior and posterior fusion using different types of instrumentation (i.e., pedicle screw, hybrid, and all-hook constructs) at our institute. Between September 2001 and July 2010 at our institute, 9 patients received anterior release/fusion and posterior fusion with different types of instrumentation, including a pedicle screw construct (n = 5), a hybrid construct (n = 3), and an all-hook construct (n = 1). We compared the pedicle screw group with the hybrid group to analyze differences in preoperative curve angle, immediate postoperative curve reduction, and latest follow-up curve angle. The mean follow-up period was 9.5 ± 2.9 years. The average age at surgery was 10.3 ± 3.9 years. The average preoperative scoliosis curve was 61.3 ± 13.8°, and the average preoperative kyphosis curve was 39.8 ± 19.7°. The average postoperative scoliosis and kyphosis curves were 29.7 ± 10.7° and 21.0 ± 13.5°, respectively. The most recent follow-up scoliosis and kyphosis curves were 43.4 ± 17.3° and 29.4 ± 18.9°, respectively. There was no significant difference in the correction angle (either coronal or sagittal), and there was no significant difference in the loss of sagittal correction between the pedicle screw construct group and the hybrid construct group. However, the patients who received pedicle screw constructs had significantly less loss of coronal correction (P < .05). Two patients with posterior instrumentation, one with an all-hook construct and the other with a hybrid construct, required surgical revision because of progression of deformity. It is difficult to intraoperatively correct dystrophic deformity and to maintain this correction after surgery. Combined anterior release/fusion and

Characterizing Myeloid Cell Activation in NF1 Vasculopathy

DTIC Science & Technology

2016-07-01

mechanistic insight and develop therapeutic targets for the prevention/treatment of neurofibromatosis type 1 (NF1) related cardiovascular disease ...therapeutic targets for the prevention/treatment of neurofibromatosis type 1 (NF1) related cardiovascular diseases . Cardiovascular disease affects upwards...superoxide; macrophages; monocytes; arteries; cardiovascular disease Major Goals and Accomplishments: Significant progress toward accomplishing

Sea-Based Infrared Scene Interpretation by Background Type Classification and Coastal Region Detection for Small Target Detection

PubMed Central

Kim, Sungho

2015-01-01

Sea-based infrared search and track (IRST) is important for homeland security by detecting missiles and asymmetric boats. This paper proposes a novel scheme to interpret various infrared scenes by classifying the infrared background types and detecting the coastal regions in omni-directional images. The background type or region-selective small infrared target detector should be deployed to maximize the detection rate and to minimize the number of false alarms. A spatial filter-based small target detector is suitable for identifying stationary incoming targets in remote sea areas with sky only. Many false detections can occur if there is an image sector containing a coastal region, due to ground clutter and the difficulty in finding true targets using the same spatial filter-based detector. A temporal filter-based detector was used to handle these problems. Therefore, the scene type and coastal region information is critical to the success of IRST in real-world applications. In this paper, the infrared scene type was determined using the relationships between the sensor line-of-sight (LOS) and a horizontal line in an image. The proposed coastal region detector can be activated if the background type of the probing sector is determined to be a coastal region. Coastal regions can be detected by fusing the region map and curve map. The experimental results on real infrared images highlight the feasibility of the proposed sea-based scene interpretation. In addition, the effects of the proposed scheme were analyzed further by applying region-adaptive small target detection. PMID:26404308

First use of patient reported outcomes measurement information system (PROMIS) measures in adults with neurofibromatosis.

PubMed

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

2017-01-01

The patient reported outcomes measurement information system (PROMIS) provides clinicians and researchers access to reliable, validated measures of physical, mental, and social well-being. The use of PROMIS can facilitate comparisons among clinical subpopulations and with the U.S. general population. We report on the first study using PROMIS measures in patients with neurofibromatosis (NF). Eighty-six adult patients (mean age = 44; 55% female; 87% white; 50% NF1, 41% NF2 and 9% schwannomatosis) completed a battery of PROMIS computerized adaptive tests (CATs). Across all PROMIS instruments, mean scores for each CAT were between 48.97 and 52.60, which is within ±0.5 SD of the U.S. general population norms. However, scores were distributed across a broad range for each PROMIS measure (±3 SDs). Clinically meaningful scores (defined >1 SD impairment) were observed in 20% (pain interference), 17% (pain behavior), 16% (physical function), 16% (anxiety), 16% (depression), 15% (satisfaction with social roles), 13% (fatigue), 6% (anger), and 5% (satisfaction with discretionary social activities) of the sample. All PROMIS measures were highly interrelated in bivariate analysis (P ≤ .001). There were no differences in PROMIS scores by disease type (NF1, NF2 and schwannomatosis), or self reported learning disabilities, or compared with the US population. Scores suggest a broad continuum of symptoms and functioning in patients with NF that is not affected by NF type, as well as interrelation among the physical and psychosocial domains as measured by PROMIS. PROMIS measures may be useful in clinical practice to monitor changes in symptoms and functioning over time, as well as in clinical trials to determine patient reported changes during drug and psychosocial clinical trials.

Sorting Five Human Tumor Types Reveals Specific Biomarkers and Background Classification Genes.

PubMed

Roche, Kimberly E; Weinstein, Marvin; Dunwoodie, Leland J; Poehlman, William L; Feltus, Frank A

2018-05-25

We applied two state-of-the-art, knowledge independent data-mining methods - Dynamic Quantum Clustering (DQC) and t-Distributed Stochastic Neighbor Embedding (t-SNE) - to data from The Cancer Genome Atlas (TCGA). We showed that the RNA expression patterns for a mixture of 2,016 samples from five tumor types can sort the tumors into groups enriched for relevant annotations including tumor type, gender, tumor stage, and ethnicity. DQC feature selection analysis discovered 48 core biomarker transcripts that clustered tumors by tumor type. When these transcripts were removed, the geometry of tumor relationships changed, but it was still possible to classify the tumors using the RNA expression profiles of the remaining transcripts. We continued to remove the top biomarkers for several iterations and performed cluster analysis. Even though the most informative transcripts were removed from the cluster analysis, the sorting ability of remaining transcripts remained strong after each iteration. Further, in some iterations we detected a repeating pattern of biological function that wasn't detectable with the core biomarker transcripts present. This suggests the existence of a "background classification" potential in which the pattern of gene expression after continued removal of "biomarker" transcripts could still classify tumors in agreement with the tumor type.

Neurofibromatosis 1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like symptoms.

PubMed

Waheed, Waqar; Nathan, Muriel H; Allen, Gilman B; Borden, Neil M; Babi, M Ali; Tandan, Rup

2015-11-03

A 37-year-old man with a known history of neurofibromatosis 1 (NF1) presented within 2 days of diarrhoeal illness followed by encephalopathy, facial twitching, hypoglycaemia, hypotension, tachycardia and low-grade fever. Examination showed multiple café-au-lait spots and neurofibromas over the trunk, arms and legs and receptive aphasia with right homonymous hemianopia, which resolved. Workup for cardiac, inflammatory and infectious aetiologies was unrevealing. A brain MRI showed gyral swelling with increased T2 fluid-attenuated inversion recovery signal and diffusion restriction in the left cerebral cortex. Neuroendocrine findings suggested panhypopituitarism with centrally derived adrenal insufficiency. Supportive treatment, hormone supplementation, antibiotics, antivirals and levetiracetam yielded clinical improvement. A follow-up brain MRI showed focal left parieto-occipital atrophy with findings of cortical laminar necrosis. In conclusion, we describe a case of NF1-associated panhypopituitarism presenting as hypoglycaemic seizures and stroke-like findings, hitherto unreported manifestations of NF1. Prompt recognition and treatment of these associated conditions can prevent devastating complications. 2015 BMJ Publishing Group Ltd.

Effect of display update interval, update type, and background on perception of aircraft separation on a cockpit display on traffic information

NASA Technical Reports Server (NTRS)

Jago, S.; Baty, D.; Oconnor, S.; Palmer, E.

1981-01-01

The concept of a cockpit display of traffic information (CDTI) includes the integration of air traffic, navigation, and other pertinent information in a single electronic display in the cockpit. Concise display symbology was developed for use in later full-mission simulator evaluations of the CDTI concept. Experimental variables used included the update interval motion of the aircraft, the update type, (that is, whether the two aircraft were updated at the same update interval or not), the background (grid pattern or no background), and encounter type (straight or curved). Only the type of encounter affected performance.

Genomic organization of the neurofibromatosis 1 gene (NF1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 regionmore » 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.« less

Four generations in a family with neurofibromatosis 1: precocious puberty and optic nerve tumor (OPT).

PubMed

Gucev, Z; Krstevska-Konstantinova, M; Tasic, V; Jancevska, A; Kirovski, I; Pop-Jordanova, N

2010-01-01

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with varied clinical manifestations. The proband is a 6-year-old boy with signs of precocious puberty. His penis was 10 cm, testicles 8 ml, pubic hair P2-3, and the genital skin was hyperpigmented. Multiple cafe au lait spots well above 5 mm were noticeable on his skin, as well as hard subcutaneous nodules, mostly on his trunk. His intelligence and hearing are normal. He has no history of seizures. Laboratory analysis showed: LH LH 1.4 mIU/ml, FSH 6.2 mIU/ml, testosterone 183 ng/ml. Bone age was 9 years. LHRH stimulation was characteristic of true precocious puberty (LH 9.8 mIU/ml and FSH 8.9 mIU/ml after 30 minutes). The MRI of the brain showed a tumor of the suprasellar region with compression of the pituitary stalk. At present the boy is 6 years old and has been treated with triptoreline acetate for 3 months. The volume of the testicles has decreased to 7 ml and a slight loss of pubic hair was noted. In addition, his mother and his grandfather exhibited dermal masses, and focal cutaneous and subcutaneous growths. The great-grand father had had the same cutaneous changes and died at the age of 75 from unrelated causes. It has already been well documented that NF is associated with an increased risk of malignancy and precocious puberty. Hence, we emphasize the need for a close and regular clinical follow-up of the OPT, puberty and patterns of growth.

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

PubMed

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

2016-12-01

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

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.

Speech-in-Noise Perception Deficit in Adults with Dyslexia: Effects of Background Type and Listening Configuration

ERIC Educational Resources Information Center

Dole, Marjorie; Hoen, Michel; Meunier, Fanny

2012-01-01

Developmental dyslexia is associated with impaired speech-in-noise perception. The goal of the present research was to further characterize this deficit in dyslexic adults. In order to specify the mechanisms and processing strategies used by adults with dyslexia during speech-in-noise perception, we explored the influence of background type,…

Multiple café au lait spots in familial patients with MAP2K2 mutation.

PubMed

Takenouchi, Toshiki; Shimizu, Atsushi; Torii, Chiharu; Kosaki, Rika; Takahashi, Takao; Saya, Hideyuki; Kosaki, Kenjiro

2014-02-01

Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated. © 2013 Wiley Periodicals, Inc.

Continuous Glucose Monitoring in Subjects with Type 1 Diabetes: Improvement in Accuracy by Correcting for Background Current

PubMed Central

Youssef, Joseph El; Engle, Julia M.; Massoud, Ryan G.; Ward, W. Kenneth

2010-01-01

Abstract Background A cause of suboptimal accuracy in amperometric glucose sensors is the presence of a background current (current produced in the absence of glucose) that is not accounted for. We hypothesized that a mathematical correction for the estimated background current of a commercially available sensor would lead to greater accuracy compared to a situation in which we assumed the background current to be zero. We also tested whether increasing the frequency of sensor calibration would improve sensor accuracy. Methods This report includes analysis of 20 sensor datasets from seven human subjects with type 1 diabetes. Data were divided into a training set for algorithm development and a validation set on which the algorithm was tested. A range of potential background currents was tested. Results Use of the background current correction of 4 nA led to a substantial improvement in accuracy (improvement of absolute relative difference or absolute difference of 3.5–5.5 units). An increase in calibration frequency led to a modest accuracy improvement, with an optimum at every 4 h. Conclusions Compared to no correction, a correction for the estimated background current of a commercially available glucose sensor led to greater accuracy and better detection of hypoglycemia and hyperglycemia. The accuracy-optimizing scheme presented here can be implemented in real time. PMID:20879968

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. Copyright © 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kayes, L.M.; Burke, W.; Bennett, R.

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 themore » 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.« less

Dilatonic parallelizable NS-NS backgrounds

NASA Astrophysics Data System (ADS)

Kawano, Teruhiko; Yamaguchi, Satoshi

2003-08-01

We complete the classification of parallelizable NS-NS backgrounds in type II supergravity by adding the dilatonic case to the result of Figueroa-O'Farrill on the non-dilatonic case. We also study the supersymmetry of these parallelizable backgrounds. It is shown that all the dilatonic parallelizable backgrounds have sixteen supersymmetries.

Clinical experience of surgically treating giant neurofibromatosis-1.

PubMed

Chen, Baoguo; Xu, Minghuo; Song, Huifeng; Gao, Quanwen

2017-02-01

The surgical treatment for giant neurofibromatosis-1 (NF-1) requires comprehensive measures. Presently, there is no systematic description of surgical treatment. Because of its high level of risk, we want to share our clinical experience. From 2011 to 2014, patients (n = 8, 5 female and 3 male patients, aging from 31 to 45 years-old) were included in the study. The tumours were located on the trunk (n = 5) or face (n = 3). In addition to routine examination, blood storage was also prepared. Preoperative consultation from related departments was critical at first. Related artery embolisation was also carried out. In the operation, we checked thromboelastography, based on which reasonable blood component transfusion was implemented. Autologous blood transfusion was also ready. An instrument of copper needle or ring ligation was used to reduce haemorrhage before the surgery. Protruding or drooping portions of the tumours were excised. A pressurised bandage was applied when the surgery was completed. After the surgery, besides the routine monitoring of vital signs, re-haemorrhage should be detected in time. Then, we should decide whether blood transfusion or surgery was required again. Expanders were implanted in one female patient with facial injuries before removing the tumour. Then, expanded flaps were applied to repair the secondary wound. According to the above clinical route, after an average of 1-year follow-up, no patients died, and other unforeseen events did not occur. Wounds healed well in all patients. The tumor was excised as much as possible. No facial nerve paralysis occurred in the facial sites. Expanded flaps necrosis WAS not encountered. It is essential to design the educational clinical route for treating NF-1 when a giant protruding tumour is advised to be excised, which can minimise the risk of surgery and assure us of the maximum range of resection. © 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wentworth, Stacy; Pinn, Melva; Bourland, J. Daniel

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 weremore » 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.« less

Schwannomatosis on a single foot: a case report.

PubMed

Min, Hak-Jin; Kim, Ki Chun; Jun, Sung Han; Lee, Young Gun

2015-06-01

Schwannomatosis has been recently recognized as the third major type of neurofibromatosis. It causes multiple schwannomas without the vestibular tumors that are diagnostic of neurofibromatosis type 2. Schwannoma is rarely found in the foot, and it is still rarer to find multiple schawannomas in a single peripheral nerve on the foot. In this article, we describe a case of schwannomatosis case on a single foot. Case report, Level IV. © 2014 The Author(s).

Neurofibromatosis, gigantism, elephantiasis neuromatosa and recurrent massive subperiosteal hematoma: a new case report and review of 7 case reports from the literature.

PubMed

Steenbrugge, F; Poffyn, B; Uyttendaele, D; Verdonk, R; Verstraete, K

2001-04-01

The authors report the case of a 13-year-old patient with neurofibromatosis (NF-I), who suffered blunt trauma to the left tibia in 1993. The diagnosis of subperiosteal hematoma was made. Treatment consisted of temporary rest. There was a recurrence in 1996, and the subperiosteal hematoma was drained. In 1997, a shortening osteotomy of the left tibia was performed. However, massive gigantism with elephantiasis of the left leg remained, causing a serious functional and cosmetic problem. In 1999, the leg was amputated above the knee. The literature is reviewed and 7 case reports are compared. The pathogenesis of subperiosteal hematoma is discussed.

[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

Health care to empower self-care in adolescents with type 1 diabetes mellitus and an immigrant minority background

PubMed Central

Boman, Åse; Bohlin, Margareta; Eklöf, Mats; Forsander, Gun; Munthe, Christian; Törner, Marianne

2017-01-01

Background: The pediatric diabetes team aims to support health, quality of life, and normal growth and development among adolescents with type 1 diabetes mellitus. Adolescents with an immigrant background have been found less successful in self-care. Previous research indicated that adolescents who had integrated the disease as a part of their self-image reasoned differently about their self-care to those who had not. Objective: The aim of this study was to identify elements in the patient–pediatrician consultations that might influence such integration of the disease among adolescents with type 1 diabetes mellitus. Methods: A total of 12 pediatrician–adolescent consultations were video-recorded and analyzed. The adolescents all had an immigrant background. Results: Integration of the disease appeared enabled when responsibility was shared; when hope, autonomy, and emotions were confirmed; and when the pediatrician asked probing questions. Letting objective data dominate the adolescent’s experiences, using risk as a motivator, neutralizing emotions in relation to having diabetes, and confirming forgetfulness, may instead inhibit disease integration. Conclusion: An extended person-centered approach with focus on the adolescent’s experiences of everyday life with a chronic disease and less attention on physical parameters in the pediatrician–adolescent consultations may increase integration of the disease. PMID:28491304

Nutrigenetics: links between genetic background and response to Mediterranean-type diets.

PubMed

Lairon, Denis; Defoort, Catherine; Martin, Jean-Charles; Amiot-Carlin, Marie-Jo; Gastaldi, Marguerite; Planells, Richard

2009-09-01

It has been substantiated that the onset of most major diseases (CVD, diabetes, obesity, cancers, etc.) is modulated by the interaction between genetic traits (susceptibility) and environmental factors, especially diet. We aim to report more specific observations relating the effects of Mediterranean-type diets on cardiovascular risk factors and the genetic background of subjects. In the first part, general concepts about nutrigenetics are briefly presented. Human genome has, overall, only marginally changed since its origin but it is thought that minor changes (polymorphisms) of common genes that occurred during evolution are now widespread in human populations, and can alter metabolic pathways and response to diets. In the second part, we report the data obtained during the Medi-RIVAGE intervention study performed in the South-East of France. Data obtained in 169 subjects at moderate cardiovascular risk after a 3-month dietary intervention indicate that some of the twenty-three single nucleotide polymorphisms (SNP) studied exhibit interactions with diets regarding changes of particular parameters after 3-month regimens. Detailed examples are presented, such as interactions between SNP in genes coding for microsomial transfer protein (MTTP) or intestinal fatty acid binding protein (FABP2) and triglyceride, LDL-cholesterol or Framigham score lowering in responses to Mediterranean-type diets. The data provided add further evidence of the interaction between particular SNP and metabolic responses to diets. Finally, improvement in dietary recommendations by taking into account known genetic variability has been discussed.

Genetics Home Reference: neurofibromatosis type 1

MedlinePlus

... Accessibility FOIA Viewers & Players U.S. Department of Health & Human Services National Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

Motivational Disturbances and Effects of L-dopa Administration in Neurofibromatosis-1 Model Mice

PubMed Central

Wozniak, David F.; Diggs-Andrews, Kelly A.; Conyers, Sara; Yuede, Carla M.; Dearborn, Joshua T.; Brown, Jacquelyn A.; Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F.; Gutmann, David H.

2013-01-01

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

Background radiation in inelastic X-ray scattering and X-ray emission spectroscopy. A study for Johann-type spectrometers

NASA Astrophysics Data System (ADS)

Paredes Mellone, O. A.; Bianco, L. M.; Ceppi, S. A.; Goncalves Honnicke, M.; Stutz, G. E.

2018-06-01

A study of the background radiation in inelastic X-ray scattering (IXS) and X-ray emission spectroscopy (XES) based on an analytical model is presented. The calculation model considers spurious radiation originated from elastic and inelastic scattering processes along the beam paths of a Johann-type spectrometer. The dependence of the background radiation intensity on the medium of the beam paths (air and helium), analysed energy and radius of the Rowland circle was studied. The present study shows that both for IXS and XES experiments the background radiation is dominated by spurious radiation owing to scattering processes along the sample-analyser beam path. For IXS experiments the spectral distribution of the main component of the background radiation shows a weak linear dependence on the energy for the most cases. In the case of XES, a strong non-linear behaviour of the background radiation intensity was predicted for energy analysis very close to the backdiffraction condition, with a rapid increase in intensity as the analyser Bragg angle approaches π / 2. The contribution of the analyser-detector beam path is significantly weaker and resembles the spectral distribution of the measured spectra. Present results show that for usual experimental conditions no appreciable structures are introduced by the background radiation into the measured spectra, both in IXS and XES experiments. The usefulness of properly calculating the background profile is demonstrated in a background subtraction procedure for a real experimental situation. The calculation model was able to simulate with high accuracy the energy dependence of the background radiation intensity measured in a particular XES experiment with air beam paths.

Multiple Schwannomas of the Spine: Review of the Schwannomatosis or Congenital Neurilemmomatosis: A Case Report.

PubMed

Lee, Sang-Hoon; Kim, Se-Hoon; Kim, Bum-Joon; Lim, Dong-Jun

2015-06-01

Schwannomas are the most common benign nerve sheath tumors originating in Schwann cells. With special conditions like neurofibromatosis type 2 or entity called schwannomatosis, patients develop multiple schwannomas. But in clinical setting, distinguishing schwannomatosis from neurofibromatosis type 2 is challengeable. We describe 58-year-old male who presented with severe neuropathic pain, from schwannomatosis featuring multiple schwannomas of spine and trunk, and underwent surgical treatment. We demonstrate his radiologic and clinical findings, and discuss about important clinical features of this condition. To confirm schwannomatosis, we performed brain magnetic resonance imaging, and took his familial history. Staged surgery was done for pathological confirmation and relief of the pain. Schwannomatosis and neurofibromatosis type 2 are similar but different disease. There are diagnostic hallmarks of these conditions, including familial history, pathology, and brain imaging. Because of different prognosis, the two diseases must be distinguished, so diagnostic tests that are mentioned above should be performed in caution.

Multiple Schwannomas of the Spine: Review of the Schwannomatosis or Congenital Neurilemmomatosis: A Case Report

PubMed Central

Lee, Sang-Hoon; Kim, Bum-Joon; Lim, Dong-Jun

2015-01-01

Schwannomas are the most common benign nerve sheath tumors originating in Schwann cells. With special conditions like neurofibromatosis type 2 or entity called schwannomatosis, patients develop multiple schwannomas. But in clinical setting, distinguishing schwannomatosis from neurofibromatosis type 2 is challengeable. We describe 58-year-old male who presented with severe neuropathic pain, from schwannomatosis featuring multiple schwannomas of spine and trunk, and underwent surgical treatment. We demonstrate his radiologic and clinical findings, and discuss about important clinical features of this condition. To confirm schwannomatosis, we performed brain magnetic resonance imaging, and took his familial history. Staged surgery was done for pathological confirmation and relief of the pain. Schwannomatosis and neurofibromatosis type 2 are similar but different disease. There are diagnostic hallmarks of these conditions, including familial history, pathology, and brain imaging. Because of different prognosis, the two diseases must be distinguished, so diagnostic tests that are mentioned above should be performed in caution. PMID:26217390

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yagle, M.K.; Parruti, G.; Xu, W.

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,more » 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.« less

Memory performance on the Auditory Inference Span Test is independent of background noise type for young adults with normal hearing at high speech intelligibility

PubMed Central

Rönnberg, Niklas; Rudner, Mary; Lunner, Thomas; Stenfelt, Stefan

2014-01-01

Listening in noise is often perceived to be effortful. This is partly because cognitive resources are engaged in separating the target signal from background noise, leaving fewer resources for storage and processing of the content of the message in working memory. The Auditory Inference Span Test (AIST) is designed to assess listening effort by measuring the ability to maintain and process heard information. The aim of this study was to use AIST to investigate the effect of background noise types and signal-to-noise ratio (SNR) on listening effort, as a function of working memory capacity (WMC) and updating ability (UA). The AIST was administered in three types of background noise: steady-state speech-shaped noise, amplitude modulated speech-shaped noise, and unintelligible speech. Three SNRs targeting 90% speech intelligibility or better were used in each of the three noise types, giving nine different conditions. The reading span test assessed WMC, while UA was assessed with the letter memory test. Twenty young adults with normal hearing participated in the study. Results showed that AIST performance was not influenced by noise type at the same intelligibility level, but became worse with worse SNR when background noise was speech-like. Performance on AIST also decreased with increasing memory load level. Correlations between AIST performance and the cognitive measurements suggested that WMC is of more importance for listening when SNRs are worse, while UA is of more importance for listening in easier SNRs. The results indicated that in young adults with normal hearing, the effort involved in listening in noise at high intelligibility levels is independent of the noise type. However, when noise is speech-like and intelligibility decreases, listening effort increases, probably due to extra demands on cognitive resources added by the informational masking created by the speech fragments and vocal sounds in the background noise. PMID:25566159

Memory performance on the Auditory Inference Span Test is independent of background noise type for young adults with normal hearing at high speech intelligibility.

PubMed

Rönnberg, Niklas; Rudner, Mary; Lunner, Thomas; Stenfelt, Stefan

2014-01-01

Listening in noise is often perceived to be effortful. This is partly because cognitive resources are engaged in separating the target signal from background noise, leaving fewer resources for storage and processing of the content of the message in working memory. The Auditory Inference Span Test (AIST) is designed to assess listening effort by measuring the ability to maintain and process heard information. The aim of this study was to use AIST to investigate the effect of background noise types and signal-to-noise ratio (SNR) on listening effort, as a function of working memory capacity (WMC) and updating ability (UA). The AIST was administered in three types of background noise: steady-state speech-shaped noise, amplitude modulated speech-shaped noise, and unintelligible speech. Three SNRs targeting 90% speech intelligibility or better were used in each of the three noise types, giving nine different conditions. The reading span test assessed WMC, while UA was assessed with the letter memory test. Twenty young adults with normal hearing participated in the study. Results showed that AIST performance was not influenced by noise type at the same intelligibility level, but became worse with worse SNR when background noise was speech-like. Performance on AIST also decreased with increasing memory load level. Correlations between AIST performance and the cognitive measurements suggested that WMC is of more importance for listening when SNRs are worse, while UA is of more importance for listening in easier SNRs. The results indicated that in young adults with normal hearing, the effort involved in listening in noise at high intelligibility levels is independent of the noise type. However, when noise is speech-like and intelligibility decreases, listening effort increases, probably due to extra demands on cognitive resources added by the informational masking created by the speech fragments and vocal sounds in the background noise.

Neurofibromatosis 2 tumor suppressor, the gene induced by valproic acid, mediates neurite outgrowth through interaction with paxillin.

PubMed

Yamauchi, Junji; Miyamoto, Yuki; Kusakawa, Shinji; Torii, Tomohiro; Mizutani, Reiko; Sanbe, Atsushi; Nakajima, Hideki; Kiyokawa, Nobutaka; Tanoue, Akito

2008-07-01

Valproic acid (VPA), the drug for bipolar disorder and epilepsy, has a potent ability to induce neuronal differentiation, yet comparatively little is presently known about the underlying mechanism. We previously demonstrated that c-Jun N-terminal kinase (JNK) phosphorylation of the focal adhesion protein paxillin mediates differentiation in N1E-115 neuroblastoma cells. Here, we show that VPA up-regulates the neurofibromatosis type 2 (NF2) tumor suppressor, merlin, to regulate neurite outgrowth through the interaction with paxillin. The inhibition of merlin function by its knockdown or expression of merlin harboring the Gln-538-to-Pro mutation, a naturally occurring NF2 missense mutation deficient in linking merlin to the actin cytoskeleton, decreases VPA-induced neurite outgrowth. Importantly, the expression of merlin by itself is not sufficient to induce neurite outgrowth, which requires co-expression with paxillin, the binding partner of merlin. In fact, the missense mutation Trp-60-to-Cys or Phe-62-to-Ser, that is deficient in binding to paxillin, reduces neurite outgrowth induced by VPA. In addition, co-expression of a paxillin construct harboring the mutation at the JNK phosphorylation site with merlin results in blunted induction of the outgrowth. We also find that the first LIM domain of paxillin is a major binding region with merlin and that expression of the isolated first LIM domain blocks the effects of VPA. Furthermore, similar findings that merlin regulates neurite outgrowth through the interaction with paxillin have been observed in several kinds of neuronal cells. These results suggest that merlin is an as yet unknown regulator of neurite outgrowth through the interaction with paxillin, providing a possibly common mechanism regulating neurite formation.

Outcomes of Spinal Fusion for Cervical Kyphosis in Children with Neurofibromatosis.

PubMed

Helenius, Ilkka J; Sponseller, Paul D; Mackenzie, William; Odent, Thierry; Dormans, John P; Asghar, Jahangir; Rathjen, Karl; Pahys, Joshua M; Miyanji, Firoz; Hedequist, Daniel; Phillips, Jonathan H

2016-11-02

Cervical kyphosis may occur with neurofibromatosis type I (NF1) and is often associated with vertebral dysplasia. Outcomes of cervical spinal fusion in patients with NF1 are not well described because of the rarity of the condition. We aimed to (1) characterize the clinical presentation of cervical kyphosis and (2) report the outcomes of posterior and anteroposterior cervical fusion for the condition in these children. The medical records and imaging studies of 22 children with NF1 who had undergone spinal fusion for cervical kyphosis (mean, 67°) at a mean age of 11 years and who had been followed for a minimum of 2 years were reviewed. Thirteen children presented with neck pain; 10, with head tilt; 9, with a previous cervical laminectomy or fusion; and 5, with a neurologic deficit. Two patients had spontaneous dislocation of the mid-cervical spine without a neurologic deficit. Eleven had scoliosis, with the major curve measuring a mean of 61°. Nine patients underwent posterior and 13 underwent anteroposterior surgery. Twenty-one received spinal instrumentation, and 1 was not treated with instrumentation. Preoperative halo traction was used for 9 patients, and it reduced the mean preoperative kyphosis by 34% (p = 0.0059). At the time of final follow-up, all spinal fusion sites had healed and the cervical kyphosis averaged 21° (mean correction, 69%; p < 0.001). The cervical kyphosis correction was significantly better after the anteroposterior procedures (83%) than after the posterior-only procedures (58%) (p = 0.031). Vertebral dysplasia and erosion continued in all 17 patients who had presented with dysplasia preoperatively. Thirteen patients had complications, including 5 new neurologic deficits and 8 cases of junctional kyphosis. Nine patients required revision surgery. Junctional kyphosis was more common in children in whom ≤5 levels had been fused (p = 0.054). Anteroposterior surgery provided better correction of cervical kyphosis than posterior spinal

Aircraft and background noise annoyance effects

NASA Technical Reports Server (NTRS)

Willshire, K. F.

1984-01-01

To investigate annoyance of multiple noise sources, two experiments were conducted. The first experiment, which used 48 subjects, was designed to establish annoyance-noise level functions for three community noise sources presented individually: jet aircraft flyovers, air conditioner, and traffic. The second experiment, which used 216 subjects, investigated the effects of background noise on aircraft annoyance as a function of noise level and spectrum shape; and the differences between overall, aircraft, and background noise annoyance. In both experiments, rated annoyance was the dependent measure. Results indicate that the slope of the linear relationship between annoyance and noise level for traffic is significantly different from that of flyover and air conditioner noise and that further research was justified to determine the influence of the two background noises on overall, aircraft, and background noise annoyance (e.g., experiment two). In experiment two, total noise exposure, signal-to-noise ratio, and background source type were found to have effects on all three types of annoyance. Thus, both signal-to-noise ratio, and the background source must be considered when trying to determine community response to combined noise sources.

Optimal background matching camouflage.

PubMed

Michalis, Constantine; Scott-Samuel, Nicholas E; Gibson, David P; Cuthill, Innes C

2017-07-12

Background matching is the most familiar and widespread camouflage strategy: avoiding detection by having a similar colour and pattern to the background. Optimizing background matching is straightforward in a homogeneous environment, or when the habitat has very distinct sub-types and there is divergent selection leading to polymorphism. However, most backgrounds have continuous variation in colour and texture, so what is the best solution? Not all samples of the background are likely to be equally inconspicuous, and laboratory experiments on birds and humans support this view. Theory suggests that the most probable background sample (in the statistical sense), at the size of the prey, would, on average, be the most cryptic. We present an analysis, based on realistic assumptions about low-level vision, that estimates the distribution of background colours and visual textures, and predicts the best camouflage. We present data from a field experiment that tests and supports our predictions, using artificial moth-like targets under bird predation. Additionally, we present analogous data for humans, under tightly controlled viewing conditions, searching for targets on a computer screen. These data show that, in the absence of predator learning, the best single camouflage pattern for heterogeneous backgrounds is the most probable sample. © 2017 The Authors.

Health care to empower self-care in adolescents with type 1 diabetes mellitus and an immigrant minority background.

PubMed

Boman, Åse; Bohlin, Margareta; Eklöf, Mats; Forsander, Gun; Munthe, Christian; Törner, Marianne

2017-01-01

The pediatric diabetes team aims to support health, quality of life, and normal growth and development among adolescents with type 1 diabetes mellitus. Adolescents with an immigrant background have been found less successful in self-care. Previous research indicated that adolescents who had integrated the disease as a part of their self-image reasoned differently about their self-care to those who had not. The aim of this study was to identify elements in the patient-pediatrician consultations that might influence such integration of the disease among adolescents with type 1 diabetes mellitus. A total of 12 pediatrician-adolescent consultations were video-recorded and analyzed. The adolescents all had an immigrant background. Integration of the disease appeared enabled when responsibility was shared; when hope, autonomy, and emotions were confirmed; and when the pediatrician asked probing questions. Letting objective data dominate the adolescent's experiences, using risk as a motivator, neutralizing emotions in relation to having diabetes, and confirming forgetfulness, may instead inhibit disease integration. An extended person-centered approach with focus on the adolescent's experiences of everyday life with a chronic disease and less attention on physical parameters in the pediatrician-adolescent consultations may increase integration of the disease.

Speech-in-noise perception deficit in adults with dyslexia: effects of background type and listening configuration.

PubMed

Dole, Marjorie; Hoen, Michel; Meunier, Fanny

2012-06-01

Developmental dyslexia is associated with impaired speech-in-noise perception. The goal of the present research was to further characterize this deficit in dyslexic adults. In order to specify the mechanisms and processing strategies used by adults with dyslexia during speech-in-noise perception, we explored the influence of background type, presenting single target-words against backgrounds made of cocktail party sounds, modulated speech-derived noise or stationary noise. We also evaluated the effect of three listening configurations differing in terms of the amount of spatial processing required. In a monaural condition, signal and noise were presented to the same ear while in a dichotic situation, target and concurrent sound were presented to two different ears, finally in a spatialised configuration, target and competing signals were presented as if they originated from slightly differing positions in the auditory scene. Our results confirm the presence of a speech-in-noise perception deficit in dyslexic adults, in particular when the competing signal is also speech, and when both signals are presented to the same ear, an observation potentially relating to phonological accounts of dyslexia. However, adult dyslexics demonstrated better levels of spatial release of masking than normal reading controls when the background was speech, suggesting that they are well able to rely on denoising strategies based on spatial auditory scene analysis strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Characterizing the microstructural basis of "unidentified bright objects" in neurofibromatosis type 1: A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis.

PubMed

Billiet, Thibo; Mädler, Burkhard; D'Arco, Felice; Peeters, Ronald; Deprez, Sabine; Plasschaert, Ellen; Leemans, Alexander; Zhang, Hui; den Bergh, Bea Van; Vandenbulcke, Mathieu; Legius, Eric; Sunaert, Stefan; Emsell, Louise

2014-01-01

The histopathological basis of "unidentified bright objects" (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1. 3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO-cNAWM pairs. No significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered. Our results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in 'extracellular-like', intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo.

Mediating factors in martial arts and combat sports: an analysis of the type of martial art, characteristics, and social background of young participants.

PubMed

Vertonghen, Jikkemien; Theeboom, Marc; Pieter, Willy

2014-02-01

To date, most studies regarding the social-psychological effects of martial arts and combat sports (MA&CS) on young people focus on measuring effects without considering mediating factors. The aim of the present study was to analyze three mediating factors that might be influential when examining outcomes of MA&CS for youth (i.e., the type of MA&CS, participants' characteristics, and social background). Young MA&CS participants (N = 477, M age = 14.0 yr., SD = 2.13) practicing judo, aikido, kick-/Thai boxing or karate, as well as their parents (N = 307), were assessed in terms of their goal orientations, aggressiveness, psychosocial behavior, and social background. It was concluded that differences exist in the characteristics and social background of participants depending on the type of MA&CS being practiced. The fact that differences in these mediating factors can be identified indicates that in future research these and possible other mediating factors should be considered when trying to determine social-psychological outcomes of MA&CS.

The impact of fibromyalgia on health status according to the types, demographic background and pain index.

PubMed

Ghavidel-Parsa, Banafsheh; Bidari, Ali; Maafi, Alireza A; Hassankhani, Amir; Hajiabbasi, Asghar; Montazeri, Ali; Sanaei, Omid; Ghalehbaghi, Babak

2016-01-01

To compare fibromyalgia (FM) core symptoms, FM impact severity and health status between the recently defined type A and type B of fibromyalgia. To compare disease impact and health status between FM patients and non-FM chronic pain control group. Finally, to compare health related quality of life and disease symptom severity by demographic background and widespread pain index (WPI). A total of 284 consecutive FM patients and 96 non-FM control patients were enrolled. The information of four questionnaires including the Fibromyalgia Survey Questionnaire (FSQ), the Fibromyalgia Impact Questionnaire (FIQ), the 12-item Short Form Health Survey (SF-12) and questionnaires regarding demographic features were collected from a local FM registry. Of all FM patients, 102 (94%) and 7 (6%) were type A and B, respectively. We found statistically significant differences in symptomatology, the FIQ scores and the SF-12 subscales across two type and control groups (p<0.001). However, when we compared these scores pairwise, except WPI there were no significant differences in other scores between type A and B. Also, there were no significant differences in FIQ and SF-12 scores across different age or educational status groups. Interestingly, patients with higher WPI had significantly higher FIQ (overall, symptom, and total) scores, worse PCS-12 and MCS-12 scores, and vice versa. Type B constitutes a minor but important component of FM that probably has a marked impact on the patient's perceived illness severity and quality of life. Further, WPI probably is the most important single indicator of disease severity and quality of life in FM.

P13.17STEREOTACTIC RADIOSURGERY WITH GAMMA KNIFE FOR NEUROFIBROMATOSIS 2-ASSOCIATED VESTIBULAR SCHWANNOMAS

PubMed Central

Presti, A. Lo; De Andrés, P.; Kusak, M.E.; De Campos, J.M.; Martínez, N.; Martínez, R.

2014-01-01

BACKGROUND: It is though that Stereotactic Radiosurgery (SRS) is less effective in achieving local tumor control in Neurofibromatosis 2 (NF2)-related vestibular schwannomas (VSs) compared with sporadic tumors. There is scarce literature on optimal dosing, clinical outcomes and eventual increased risk for malignant transformation among these patients. It is also possible that radiation induced tumors, in patients bearing an abnormality in a tumor suppressor gene, are misinterpreted as part of the natural history of NF2, where new tumors are expected to develop. OBJECTIVE: To evaluate the results of Gamma Knife (GK) Radiosurgery in the management of NF2-related VSs versus the sporadic VSs group treated at the same Center. METHOD: A prospectively maintained clinical database including all patients who underwent SRS for VSs was reviewed, and all subjects fulfilling the Manchester diagnostic criteria for NF2 were identified. Between 1994 and 2012, 35 patients with NF2 underwent SRS for 55 presumed VSs at our institution. The mean age at time of treatment was 30.8 years and the mean follow-up period was 4.3 years (1-14.75 years). The median margin dose used was 12 Gy and a total of 62 treatments were performed. Outcome measures, including imaging progression, hearing preservation, trigeminal and facial nerve function, were analyzed. RESULTS: Regarding tumor control 53.4% remained unchanged in size, 22.4% were smaller and 22.4% showed progression requiring further microsurgical resection or SRS. Hearing worsening occurred in 37% of tumors; 2 patients developed facial neuropathy, one of them bilateral and the other transient; trigeminal neuropathy occurred in 4 patients, one of them with previous mild impairment. No cases of malignant transformation were reported. Compared to the sporadic VSs group, NF2 patients showed lower local tumor control and higher incidence of facial and trigeminal neuropathy. CONCLUSION: NF2-related VSs treated with GK show worse clinical and

The Role of Drosophila Merlin in the Control of Mitosis Exit and Development

DTIC Science & Technology

2006-07-01

schwannomas and is associated with mutations in the tumor suppressor gene called the neurofibromatosis type 2 (NF2) gene (Chang et al., 2005; Neff...been shown to associate with endocytic compartments and because mutations in the genes , such as clathrin and ff16, that are known to be important... mutations in the Drosophila homologues of the human Neurofibromatosis 2 and yeast CDC42 genes using a simple and efficient reverse-genetic method. Genetics

Electroconvulsive therapy for medication-refractory depression in a patient with ruptured intracranial dermoid cyst, meningioma, and neurofibromatosis.

PubMed

Thukral-Mahajan, Priyanka; Shah, Nilesh; Kalra, Gurvinder; Andrade, Chittaranjan

2017-01-01

Electroconvulsive therapy (ECT) is considered relatively contraindicated in patients with intracranial space-occupying lesions. A 53-year-old male presented with a 5-year history of medication-refractory major depressive disorder. Brain imaging findings suggested the presence of a ruptured dermoid cyst in the transverse sinus and a calcified meningioma in the temporal lobe sulcal space. There was no evidence of mass effect. Neurofibromatosis was the only other clinical condition present. The patient had no clinical neurological deficits. Since the depression was severe and he was suicidal, ECT was advised. There was a substantial improvement after four bilateral and then eight right unilateral brief-pulse ECTs administered on alternate days, thrice weekly. There were no complications associated with ECT. The treatment gains were maintained with maintenance antidepressant medication at a 1-year follow-up. This is probably the first reported case of the use of ECT in a medication-refractory, severely depressed patient with a ruptured intracranial dermoid cyst and with a calcifying meningioma. The results testify to the safety of ECT even in high-risk patients.

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

PubMed

Riklin, Eric; Talaei-Khoei, 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. © 2017 Wiley Periodicals, Inc.

Mortality Associated with Neurofibromatosis 1: A Cohort Study of 1895 Patients in 1980-2006 in France

PubMed Central

2011-01-01

Background Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006. Methods Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death. Results Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%). Conclusions We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males. PMID:21542925

Wounding-Induced Manifestations of Type 1 Neurofibromatosis

DTIC Science & Technology

2001-07-01

hairless mice induced by topical dimethylbenzanthracene., Exp. Cell Biol. 57: 292-9, 1989. Vogel, K. S., Klesse, L. J., Velasco- Miguel , S., Meyers, K... Santoro IM, Kordich JJ, Gismondi V, Trzepacz C, Badiali M, Giangaspero F, Balko MG, Graham JS, Ratner N, Lowy AM, Varesco L, Groden J. (2001) A

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

2018-01-01

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

A low-background piston-cylinder-type hybrid high pressure cell for muon-spin rotation/relaxation experiments

NASA Astrophysics Data System (ADS)

Shermadini, Z.; Khasanov, R.; Elender, M.; Simutis, G.; Guguchia, Z.; Kamenev, K. V.; Amato, A.

2017-10-01

A low background double-wall piston-cylinder-type pressure cell is developed at the Paul Scherrer Institute. The cell is made from BERYLCO-25 (beryllium copper) and MP35N nonmagnetic alloys with the design and dimensions which are specifically adapted to muon-spin rotation/relaxation (μSR) measurements. The mechanical design and performance of the pressure cell are evaluated using finite-element analysis (FEA). By including the measured stress-strain characteristics of the materials into the finite-element model, the cell dimensions are optimized with the aim to reach the highest possible pressure while maintaining the sample space large (6 mm in diameter and 12 mm high). The presented unconventional design of the double-wall piston-cylinder pressure cell with a harder outer MP35N sleeve and a softer inner CuBe cylinder enables pressures of up to 2.6 GPa to be reached at ambient temperature, corresponding to 2.2 GPa at low temperatures without any irreversible damage to the pressure cell. The nature of the muon stopping distribution, mainly in the sample and in the CuBe cylinder, results in a low-background μSR signal.

Effects of flicker rate, complexity, and color combinations of Chinese characters and backgrounds on visual search performance with varying flicker types.

PubMed

Huang, Kuo-Chen; Lin, Rung-Tai; Wu, Chih-Fu

2011-08-01

This study investigated the effects of number of strokes in Chinese characters, flicker rate, flicker type, and character/background color combination on search performance. 37 participants ages 14 to 18 years were randomly assigned to each flicker-type condition. The search field contained 36 characters arranged in a 6 x 6 matrix. Participants were asked to search for the target characters among the surrounding distractors and count how many target characters were displayed in the search array. Analysis indicated that the character/background color combination significantly affected search times. The color combinations of white/purple and white/green yielded search times greater than those for black/white and black/yellow combinations. A significant effect for flicker type on search time was also identified. Rotating characters facilitated search time, compared with twinkling ones. The number of strokes and the flicker rates also had positive effects on search performances. For flicker rate, the search accuracy for 0.5 Hz was greater than that for 1.0 Hz, and the latter was also greater than that for 2.0 Hz. Results are applicable to web advertisement designs containing dynamic characters, in terms of how to best capture readers' attention by various means of dynamic character presentation.

Familial Investigations of Childhood Cancer Predisposition

ClinicalTrials.gov

2018-01-03

Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease

Personal Background Knowledge Influences Cross-Cultural Understanding

ERIC Educational Resources Information Center

Lin, Xiaodong; Bransford, John D.

2010-01-01

Purpose of the Study: The purpose of the study was to investigate how two types of videos, personal background knowledge (PBK) and general background knowledge (GBK), affect people's interpretation of a classroom problem case that involved a disconnection between a foreign college professor and her students. The PBK video described the professor's…

Recovery from bleaching is mediated by threshold densities of background thermo-tolerant symbiont types in a reef-building coral

PubMed Central

Bay, Line K.; Doyle, Jason; Logan, Murray; Berkelmans, Ray

2016-01-01

Sensitive molecular analyses show that most corals host a complement of Symbiodinium genotypes that includes thermo-tolerant types in low abundance. While tolerant symbiont types are hypothesized to facilitate tolerance to temperature and recovery from bleaching, empirical data on their distribution and relative abundance in corals under ambient and stress conditions are still rare. We quantified visual bleaching and mortality of coral hosts, along with relative abundance of C- and D-type Symbiodinium cells in 82 Acropora millepora colonies from three locations on the Great Barrier Reef transplanted to a central inshore site over a 13 month period. Our analyses reveal dynamic change in symbiont associations within colonies and among populations over time. Coral bleaching and declines in C- but not D-type symbionts were observed in transplanted corals. Survival and recovery of 25% of corals from one population was associated with either initial D-dominance or an increase in D-type symbionts that could be predicted by a minimum pre-stress D : C ratio of 0.003. One-third of corals from this population became D dominated at the bleached stage despite no initial detection of this symbiont type, but failed to recover and died in mid to late summer. These results provide a predictive threshold minimum density of background D-type symbionts in A. millepora, above which survival following extreme thermal stress is increased. PMID:27429786

[PATOGENETIC VALUE OF VIOLATIONS FROM GLUTATHIONE SYSTEM AT THE PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS ON A BACKGROUND OF DIABETES MELLITUS TYPE II].

PubMed

Kostev, I V; Teryoshin, V A; Sotckaya, Ya A; Homutyanskay, N I; Dolgopolova, E V; Salamech, K A

2015-01-01

At the patients with nonalcoholic steatohepatitis on a background of diabetes mellitus type 11, after completion of the generally accepted medical treatment there was no normalization of indexes of the glutation system (the level of recovered glutation and activity of enzymes the glutation redox--system was saved decreased), that in a clinical plan was represented in a presence unstable clinical and biochemical remission of disease.

[PATOGENETIC VALUE OF VIOLATIONS FROM GLUTATHIONE SYSTEM AT THE PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS ON A BACKGROUND OF DIABETES MELLITUS TYPE II].

PubMed

Sotskaya, Ya A; Homutyanskaya, N I; Dolgopolova, E V; Salamekh, K A

2015-01-01

At the patients with nonalcoholic steatohepatitis on a background of diabetes mellitus type II, after completion of the generally accepted medical treatment there was no normalization of indexes of the glutation system (the level of recovered glutation and activity of enzymes the glutation redox-system was saved decreased), that in a clinical plan was represented in.a presence unstable clinical and biochemical remission of disease.

Tibial Bowing and Pseudarthrosis in Neurofibromatosis Type 1

DTIC Science & Technology

2015-01-01

controlling for age and sex was used. However, there were no statistically significant differences between NF1 individuals with and without tibial...Dinorah Friedmann-Morvinski (The Salk Institute) presented a different model of glioblastoma in which tumors were induced from fully differentiated...a driver of Schwann cell tumorigenesis. Induction ofWnt signaling was sufficient to induce a transformed phenotype in human Schwann cells, while

Neurofibromatosis Type 2: Information for Patients and Families

MedlinePlus

... symptoms of NF2 include ringing in the ears (tinnitus), gradual hearing loss, and balance problems. Schwannomatosis is ... all, of the following: • Ringing in the ears (tinnitus) • Hearing loss • Problems with balance • Facial weakness • Brain ...

Visuospatial Processing in Children with Neurofibromatosis Type 1

ERIC Educational Resources Information Center

Clements-Stephens, Amy M.; Rimrodt, Sheryl L.; Gaur, Pooja; Cutting, Laurie E.

2008-01-01

Neuroimaging studies investigating the neural network of visuospatial processing have revealed a right hemisphere network of activation including inferior parietal lobe, dorsolateral prefrontal cortex, and extrastriate regions. Impaired visuospatial processing, indicated by the Judgment of Line Orientation (JLO), is commonly seen in individuals…

Recurrent knee pain in an athletic adult: multiple schwannomas secondary to schwannomatosis: a case report.

PubMed

Maceroli, Michael; Uglialoro, Anthony D; Beebe, Kathleen S; Benevenia, Joseph

2010-11-01

Schwannomatosis has been used to describe patients with multiple nonvestibular schwannomas with no associated features of neurofibromatosis type 2. In our case, a 28-year-old athletic man underwent a right knee excisional biopsy for multifocal, benign schwannomatosis. After being asymptomatic for 4 years postresection, he returned to our musculoskeletal oncology service. Imaging studies revealed local recurrence identical to his initial presentation. Excisional biopsy of discrete masses was performed and histologic examination revealed recurrent benign schwannomatosis. To our knowledge, this is the second reported case of recurrent benign schwannomatosis. We review schwannomatosis, including its etiology, radiographic features, and relationship to neurofibromatosis.

A review on natural background radiation

PubMed Central

Shahbazi-Gahrouei, Daryoush; Gholami, Mehrdad; Setayandeh, Samaneh

2013-01-01

The world is naturally radioactive and approximately 82% of human-absorbed radiation doses, which are out of control, arise from natural sources such as cosmic, terrestrial, and exposure from inhalation or intake radiation sources. In recent years, several international studies have been carried out, which have reported different values regarding the effect of background radiation on human health. Gamma radiation emitted from natural sources (background radiation) is largely due to primordial radionuclides, mainly 232Th and 238U series, and their decay products, as well as 40K, which exist at trace levels in the earth's crust. Their concentrations in soil, sands, and rocks depend on the local geology of each region in the world. Naturally occurring radioactive materials generally contain terrestrial-origin radionuclides, left over since the creation of the earth. In addition, the existence of some springs and quarries increases the dose rate of background radiation in some regions that are known as high level background radiation regions. The type of building materials used in houses can also affect the dose rate of background radiations. The present review article was carried out to consider all of the natural radiations, including cosmic, terrestrial, and food radiation. PMID:24223380

New families of interpolating type IIB backgrounds

NASA Astrophysics Data System (ADS)

Minasian, Ruben; Petrini, Michela; Zaffaroni, Alberto

2010-04-01

We construct new families of interpolating two-parameter solutions of type IIB supergravity. These correspond to D3-D5 systems on non-compact six-dimensional manifolds which are mathbb{T}2 fibrations over Eguchi-Hanson and multi-center Taub-NUT spaces, respectively. One end of the interpolation corresponds to a solution with only D5 branes and vanishing NS three-form flux. A topology changing transition occurs at the other end, where the internal space becomes a direct product of the four-dimensional surface and the two-torus and the complexified NS-RR three-form flux becomes imaginary self-dual. Depending on the choice of the connections on the torus fibre, the interpolating family has either mathcal{N}=2 or mathcal{N}=1 supersymmetry. In the mathcal{N}=2 case it can be shown that the solutions are regular.

Radiosensitivity of fibroblasts obtained from a cafe-au-lait spot and normal-appearing skin of a patient with neurofibromatosis (NF-6)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hannan, M.A.; Smith, B.P.; Sigut, D.

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 showedmore » 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.« less

Appearance concerns among women with neurofibromatosis: examining sexual/bodily and social self-consciousness.

PubMed

Smith, Kelly B; Wang, Daphne L; Plotkin, Scott R; Park, Elyse R

2013-12-01

Neurofibromatosis (NF) 1 and 2 have distinct appearance effects, yet little research has examined patients' appearance concerns. We assessed appearance concerns and self-consciousness, self-esteem, and loneliness among women with NF. Women with NF1 (n = 79) and NF2 (n = 48) completed the Derriford Appearance Scale to assess appearance concerns and sexual/bodily and social self-consciousness, Rosenberg Self-Esteem Scale, and UCLA Loneliness Scale. Women's appearance concerns were coded to determine whether they were NF-related and whether psychosocial factors contributed to the concerns. A total of 85% of women reported appearance concerns, many of which were NF-related and attributed to psychosocial factors. Women with NF1 reported significantly more sexual/bodily self-consciousness but similar levels of social self-consciousness compared with women with NF2. Significantly higher sexual/bodily self-consciousness was found among married/cohabiting women regardless of NF group. Compared with general population norms and breast cancer survivors (BCS), women with NF1 reported significantly greater sexual/bodily and social self-consciousness. Women with NF2 reported less sexual/bodily self-consciousness compared with population norms, yet tended to report greater sexual/bodily self-consciousness than BCS. Women with NF2 reported significantly greater social self-consciousness compared with population norms and BCS. For both NF1 and NF2, higher levels of sexual/bodily and social self-consciousness were related to lower self-esteem and higher levels of social self-consciousness to more loneliness. Appearance concerns are prevalent, and social self-consciousness is high, among women with NF1 and NF2. Women with NF1 compared with NF2 experience more sexual/bodily self-consciousness. Providers should assess the impact of NF on women's self-perceptions and address sexual, body image, and social concerns. Copyright © 2013 John Wiley & Sons, Ltd.

Synergistic Interplay between Curcumin and Polyphenol-Rich Foods in the Mediterranean Diet: Therapeutic Prospects for Neurofibromatosis 1 Patients.

PubMed

Esposito, Teresa; Schettino, Carla; Polverino, Paola; Allocca, Salvatore; Adelfi, Laura; D'Amico, Alessandra; Capaldo, Guglielmo; Varriale, Bruno; Di Salle, Anna; Peluso, Gianfranco; Sorrentino, Giuseppe; Lus, Giacomo; Sampaolo, Simone; Di Iorio, Giuseppe; Melone, Mariarosa Anna Beatrice

2017-07-21

Neurofibromas are the hallmark lesions in Neurofibromatosis 1 (NF1); these tumors are classified as cutaneous, subcutaneous and plexiform. In contrast to cutaneous and subcutaneous neurofibromas, plexiform neurofibromas can grow quickly and progress to malignancy. Curcumin, a turmeric-derived polyphenol, has been shown to interact with several molecular targets implicated in carcinogenesis. Here, we describe the impact of different dietary patterns, namely Mediterranean diet (MedDiet) compared to the Western diet (WesDiet), both with or without curcumin, on NF1 patients' health. After six months, patients adopting a traditional MedDiet enriched with 1200 mg curcumin per day (MedDietCurcumin) presented a significant reduction in the number and volume of cutaneous neurofibromas; these results were confirmed in subsequent evaluations. Notably, in one patient, a large cranial plexiform neurofibroma exhibited a reduction in volume (28%) confirmed by Magnetic Resonance Imaging. Conversely, neither unenriched MedDiet nor WesDiet enriched with curcumin exhibited any significant positive effect. We hypothesize that the combination of a polyphenol-rich Mediterranean diet and curcumin was responsible for the beneficial effect observed on NF1. This is, to the best of our knowledge, the first experience with curcumin supplementation in NF1 patients. Our report suggests that an integrated nutritional approach may effectively aid in the management of NF1.

Physiologic correlates to background noise acceptance

NASA Astrophysics Data System (ADS)

Tampas, Joanna; Harkrider, Ashley; Nabelek, Anna

2004-05-01

Acceptance of background noise can be evaluated by having listeners indicate the highest background noise level (BNL) they are willing to accept while following the words of a story presented at their most comfortable listening level (MCL). The difference between the selected MCL and BNL is termed the acceptable noise level (ANL). One of the consistent findings in previous studies of ANL is large intersubject variability in acceptance of background noise. This variability is not related to age, gender, hearing sensitivity, personality, type of background noise, or speech perception in noise performance. The purpose of the current experiment was to determine if individual differences in physiological activity measured from the peripheral and central auditory systems of young female adults with normal hearing can account for the variability observed in ANL. Correlations between ANL and various physiological responses, including spontaneous, click-evoked, and distortion-product otoacoustic emissions, auditory brainstem and middle latency evoked potentials, and electroencephalography will be presented. Results may increase understanding of the regions of the auditory system that contribute to individual noise acceptance.

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. © 2015 Japanese Dermatological Association.

Radon-related Backgrounds in the LUX Dark Matter Search

NASA Astrophysics Data System (ADS)

Bradley, A.; Akerib, D. S.; Araújo, H. M.; Bai, X.; Bailey, A. J.; Balajthy, J.; Bernard, E.; Bernstein, A.; Byram, D.; Cahn, S. B.; Carmona-Benitez, M. C.; Chan, C.; Chapman, J. J.; Chiller, A. A.; Chiller, C.; Coffey, T.; Currie, A.; de Viveiros, L.; Dobi, A.; Dobson, J.; Druszkiewicz, E.; Edwards, B.; Faham, C. H.; Fiorucci, S.; Flores, C.; Gaitskell, R. J.; Gehman, V. M.; Ghag, C.; Gibson, K. R.; Gilchriese, M. G. D.; Hall, C.; Hertel, S. A.; Horn, M.; Huang, D. Q.; Ihm, M.; Jacobsen, R. G.; Kazkaz, K.; Knoche, R.; Larsen, N. A.; Lee, C.; Lindote, A.; Lopes, M. I.; Malling, D. C.; Mannino, R.; McKinsey, D. N.; Mei, D.-M.; Mock, J.; Moongweluwan, M.; Morad, J.; Murphy, A. St. J.; Nehrkorn, C.; Nelson, H.; Neves, F.; Ott, R. A.; Pangilinan, M.; Parker, P. D.; Pease, E. K.; Pech, K.; Phelps, P.; Reichhart, L.; Shutt, T.; Silva, C.; Solovov, V. N.; Sorensen, P.; O'Sullivan, K.; Sumner, T. J.; Szydagis, M.; Taylor, D.; Tennyson, B.; Tiedt, D. R.; Tripathi, M.; Uvarov, S.; Verbus, J. R.; Walsh, N.; Webb, R.; White, J. T.; Witherell, M. S.; Wolfs, F. L. H.; Woods, M.; Zhang, C.

The LUX detector is currently in operation at the Davis Campus at the 4850' level of the Sanford Underground Research Facility (SURF) in Lead, SD to directly search for WIMP dark matter. Knowing the type and rate of backgrounds is critical in a rare, low energy event search, and LUX was designed, constructed, and deployed to mitigate backgrounds, both internal and external. An important internal background are decays of radon and its daughters. These consist of alpha decays, which are easily tagged and are a tracer of certain backgrounds, and beta decays, some of which are not as readily tagged and present a background for the WIMP search. We report on studies of alpha decay and discuss implications for the WIMP search.

Mind-body therapy via videoconferencing in patients with neurofibromatosis: An RCT.

PubMed

Vranceanu, Ana-Maria; Riklin, Eric; Merker, Vanessa L; Macklin, Eric A; Park, Elyse R; Plotkin, Scott R

2016-08-23

To test, within a single-blind randomized controlled trial, the feasibility, acceptability, efficacy, and durability of a mind-body program (the Relaxation Response Resiliency Program for neurofibromatosis [3RP-NF]) vs an attention placebo control (Health Enhancement Program for NF [HEP-NF]), both delivered via group videoconferencing. Sixty-three patients completed baseline assessments and were randomized. Primary outcomes were physical health and psychological quality of life (QoL), measured by the WHOQOL-BREF (World Health Organization QoL abbreviated instrument). Secondary outcomes were social relations and environment QoL, depression, anxiety, pain intensity, and pain interference. Sixty-three participants completed the intervention (100%) and 52 the 6-month follow-up (82.5%). Acceptability was 4.1 (5-point scale). Patients in the 3RP-NF showed greater improvement in physical health QoL (7.69; 95% confidence interval [CI]: 0.29-15.10; p = 0.040), psychological QoL (5.57; 95% CI: 0.17-11.34; p = 0.056), social relations QoL (10.95; 95% CI: 1.57-20.31; p = 0.021), environment QoL (8.02; 95% CI: 2.57-13.48; p = 0.005), and anxiety (-2.32; 95% CI: -3.96 to 0.69; p = 0.006) compared to those in HEP-NF, and gains were maintained at follow-up. Patients in the 3RP-NF did not improve more than those in HEP-NF on depression, with both groups showing improvement. Patients in the 3RP-NF with baseline pain ≥5 of 10 showed improvement in pain intensity from baseline to posttest (1.30; 95% CI: -2.26 to -0.34; p = 0.009) with effects maintained at follow-up; this improvement was not greater than that in HEP-NF. There were more treatment responders in the 3RP-NF group (p < 0.05). The 3RP-NF delivered via videoconferencing was highly feasible and accepted by patients, and resulted in sustained improvement in QoL. This study provides Class II evidence that for patients with NF, a mind-body program is superior to an attention placebo control in improving QoL. © 2016 American

Background Model for the Majorana Demonstrator

NASA Astrophysics Data System (ADS)

Cuesta, C.; Abgrall, N.; Aguayo, E.; Avignone, F. T.; Barabash, A. S.; Bertrand, F. E.; Boswell, M.; Brudanin, V.; Busch, M.; Byram, D.; Caldwell, A. S.; Chan, Y.-D.; Christofferson, C. D.; Combs, D. C.; Detwiler, J. A.; Doe, P. J.; Efremenko, Yu.; Egorov, V.; Ejiri, H.; Elliott, S. R.; Fast, J. E.; Finnerty, P.; Fraenkle, F. M.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, V. E.; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J.; Leviner, L. E.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Meijer, S.; Mertens, S.; Nomachi, M.; Orrell, J. L.; O'Shaughnessy, C.; Overman, N. R.; Phillips, D. G.; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, A. G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Suriano, A. M.; Thompson, J.; Timkin, V.; Tornow, W.; Trimble, J. E.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Young, A. R.; Yu, C.-H.; Yumatov, V.

The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.

Background model for the Majorana Demonstrator

DOE PAGES

Cuesta, C.; Abgrall, N.; Aguayo, E.; ...

2015-01-01

The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example usingmore » powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.« less

Gamma-ray background induced by atmospheric neutrons

NASA Astrophysics Data System (ADS)

Ma, Y.-Q.

1984-03-01

A small piggyback detector system is used to study the reduction of gamma-ray background induced by atmospheric neutrons in the type of actively shielded gamma-ray spectroscopes. The system consists of two 1.5 x 1.5 arcsec NaI crystal units, one of which is surrounded by some neutron shield material. The results of a balloon flight in 1981 are presented. The data show that a shield of 3 cm-thick pure paraffin cannot reduce the gamma-ray background. On the contrary, it may even cause some enhancement.

Neurocutaneous Syndromes

MedlinePlus

... NF2), and Schwannomatosis. NF1 is the most common, accounting for about 90% of all cases. Neurofibromatosis Type ... A child with complications involving the eye, nervous system, spine, or bones will be referred to a ...

Radon-related backgrounds in the LUX dark matter search

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, A.; Akerib, D. S.; Araújo, H. M.

The LUX detector is currently in operation at the Davis Campus at the 4850’ level of the Sanford Underground Research Facility (SURF) in Lead, SD to directly search for WIMP dark matter. Knowing the type and rate of backgrounds is critical in a rare, low energy event search, and LUX was designed, constructed, and deployed to mitigate backgrounds, both internal and external. An important internal background are decays of radon and its daughters. These consist of alpha decays, which are easily tagged and are a tracer of certain backgrounds, and beta decays, some of which are not as readily taggedmore » and present a background for the WIMP search. We report on studies of alpha decay and discuss implications for the WIMP search.« less

Radon-related backgrounds in the LUX dark matter search

DOE PAGES

Bradley, A.; Akerib, D. S.; Araújo, H. M.; ...

2015-01-01

The LUX detector is currently in operation at the Davis Campus at the 4850’ level of the Sanford Underground Research Facility (SURF) in Lead, SD to directly search for WIMP dark matter. Knowing the type and rate of backgrounds is critical in a rare, low energy event search, and LUX was designed, constructed, and deployed to mitigate backgrounds, both internal and external. An important internal background are decays of radon and its daughters. These consist of alpha decays, which are easily tagged and are a tracer of certain backgrounds, and beta decays, some of which are not as readily taggedmore » and present a background for the WIMP search. We report on studies of alpha decay and discuss implications for the WIMP search.« less

Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis.

PubMed

Smith, Miriam J; Esparza, Sonia; Merker, Vanessa L; Muzikansky, Alona; Bredella, Miriam A; Harris, Gordon J; Kassarjian, Ara; Cai, Wenli; Walker, James A; Mautner, Victor F; Plotkin, Scott R

2013-05-01

Neurofibromatosis 1 (NF1), NF2, and schwannomatosis are characterized by a predisposition to develop multiple neurofibromas and schwannomas. Currently, there is no blood test to estimate tumor burden in patients with these disorders. We explored whether S100β would act as a biomarker of tumor burden in NF since S100β is a classic immunohistochemical marker of astrocytes, oligodendrocytes and Schwann cells and a small study showed S100β concentrations correlate with the volume of vestibular schwannomas. We calculated whole-body tumor burden in subjects with NF1, NF2, and schwannomatosis using whole-body MRI (WBMRI) and measured the concentration of S100β in plasma using ELISA. We used chi-square tests and Spearman rank correlations to test the relationship between S100β levels and whole-body tumor burden. 127 consecutive patients were enrolled in the study (69 NF1 patients, 28 NF2 patients, and 30 schwannomatosis patients). The median age was 40years, 43% were male, and median whole-body tumor volume was 26.9mL. There was no relationship between the presence of internal tumors and the presence of detectable S100β in blood for the overall group or for individual diagnoses (p>0.05 by chi-square for all comparisons). Similarly, there was no correlation between whole-body tumor volume and S100β concentration for the overall group or for individual diagnoses (p>0.05 by Spearman for all comparisons). Plasma S100β is not a useful biomarker for tumor burden in the neurofibromatoses. Further work is needed to identify a reliable biomarker of tumor burden in NF patients. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Effects of Elevated Pax6 Expression and Genetic Background on Mouse Eye Development

PubMed Central

Chanas, Simon A.; Collinson, J. Martin; Ramaesh, Thaya; Dorà, Natalie; Kleinjan, Dirk A.; Hill, Robert E.; West, John D.

2009-01-01

Purpose To analyze the effects of Pax6 overexpression and its interaction with genetic background on eye development. Methods Histologic features of eyes from hemizygous PAX77+/− transgenic (high Pax6 gene dose) and wild-type mice were compared on different genetic backgrounds. Experimental PAX77+/−↔wild-type and control wild-type↔wild-type chimeras were analyzed to investigate the causes of abnormal eye development in PAX77+/− mice. Results PAX77+/− mice showed an overlapping but distinct spectrum of eye abnormalities to Pax6+/− heterozygotes (low Pax6 dose). Some previously reported PAX77+/− eye abnormalities did not occur on all three genetic backgrounds examined. Several types of eye abnormalities occurred in the experimental PAX77+/−↔wild-type chimeras, and they occurred more frequently in chimeras with higher contributions of PAX77+/− cells. Groups of RPE cells intruded into the optic nerve sheath, indicating that the boundary between the retina and optic nerve may be displaced. Both PAX77+/− and wild-type cells were involved in this ingression and in retinal folds, suggesting that neither effect was cell-autonomous. Cell-autonomous effects included failure of PAX77+/− and wild-type cells to mix normally and overrepresentation of PAX77+/− in the lens epithelium and RPE. Conclusions The extent of PAX77+/− eye abnormalities depended on PAX77+/− genotype, genetic background, and stochastic variation. Chimera analysis identified two types of cell-autonomous effects of the PAX77+/− genotype. Abnormal cell mixing between PAX77+/− and wild-type cells suggests altered expression of cell surface adhesion molecules. Some phenotypic differences between PAX77+/−↔wild-type and Pax6+/−↔wild-type chimeras may reflect differences in the levels of PAX77+/− and Pax6+/− contributions to chimeric lenses. PMID:19387074

Evaluation of a Method Using Three Genomic Guided Escherichia coli Markers for Phylogenetic Typing of E. coli Isolates of Various Genetic Backgrounds

PubMed Central

Hamamoto, Kouta; Ueda, Shuhei; Yamamoto, Yoshimasa

2015-01-01

Genotyping and characterization of bacterial isolates are essential steps in the identification and control of antibiotic-resistant bacterial infections. Recently, one novel genotyping method using three genomic guided Escherichia coli markers (GIG-EM), dinG, tonB, and dipeptide permease (DPP), was reported. Because GIG-EM has not been fully evaluated using clinical isolates, we assessed this typing method with 72 E. coli collection of reference (ECOR) environmental E. coli reference strains and 63 E. coli isolates of various genetic backgrounds. In this study, we designated 768 bp of dinG, 745 bp of tonB, and 655 bp of DPP target sequences for use in the typing method. Concatenations of the processed marker sequences were used to draw GIG-EM phylogenetic trees. E. coli isolates with identical sequence types as identified by the conventional multilocus sequence typing (MLST) method were localized to the same branch of the GIG-EM phylogenetic tree. Sixteen clinical E. coli isolates were utilized as test isolates without prior characterization by conventional MLST and phylogenetic grouping before GIG-EM typing. Of these, 14 clinical isolates were assigned to a branch including only isolates of a pandemic clone, E. coli B2-ST131-O25b, and these results were confirmed by conventional typing methods. Our results suggested that the GIG-EM typing method and its application to phylogenetic trees might be useful tools for the molecular characterization and determination of the genetic relationships among E. coli isolates. PMID:25809972

Accuracy of Cochlear Implant Recipients on Speech Reception in Background Music

PubMed Central

Gfeller, Kate; Turner, Christopher; Oleson, Jacob; Kliethermes, Stephanie; Driscoll, Virginia

2012-01-01

Objectives This study (a) examined speech recognition abilities of cochlear implant (CI) recipients in the spectrally complex listening condition of three contrasting types of background music, and (b) compared performance based upon listener groups: CI recipients using conventional long-electrode (LE) devices, Hybrid CI recipients (acoustic plus electric stimulation), and normal-hearing (NH) adults. Methods We tested 154 LE CI recipients using varied devices and strategies, 21 Hybrid CI recipients, and 49 NH adults on closed-set recognition of spondees presented in three contrasting forms of background music (piano solo, large symphony orchestra, vocal solo with small combo accompaniment) in an adaptive test. Outcomes Signal-to-noise thresholds for speech in music (SRTM) were examined in relation to measures of speech recognition in background noise and multi-talker babble, pitch perception, and music experience. Results SRTM thresholds varied as a function of category of background music, group membership (LE, Hybrid, NH), and age. Thresholds for speech in background music were significantly correlated with measures of pitch perception and speech in background noise thresholds; auditory status was an important predictor. Conclusions Evidence suggests that speech reception thresholds in background music change as a function of listener age (with more advanced age being detrimental), structural characteristics of different types of music, and hearing status (residual hearing). These findings have implications for everyday listening conditions such as communicating in social or commercial situations in which there is background music. PMID:23342550

Double NF1 Inactivation Affects Adrenocortical Function in NF1Prx1 Mice and a Human Patient

PubMed Central

Kobus, Karolina; Hartl, Daniela; Ott, Claus Eric; Osswald, Monika; Huebner, Angela; von der Hagen, Maja; Emmerich, Denise; Kühnisch, Jirko; Morreau, Hans; Hes, Frederik J.; Mautner, Victor F.; Harder, Anja; Tinschert, Sigrid; Mundlos, Stefan; Kolanczyk, Mateusz

2015-01-01

Background Neurofibromatosis type I (NF1, MIM#162200) is a relatively frequent genetic condition, which predisposes to tumor formation. Apart from tumors, individuals with NF1 often exhibit endocrine abnormalities such as precocious puberty (2,5–5% of NF1 patients) and some cases of hypertension (16% of NF1 patients). Several cases of adrenal cortex adenomas have been described in NF1 individuals supporting the notion that neurofibromin might play a role in adrenal cortex homeostasis. However, no experimental data were available to prove this hypothesis. Materials and Methods We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient. Results In Nf1Prx1 mice Nf1 is inactivated in the developing limbs, head mesenchyme as well as in the adrenal gland cortex, but not the adrenal medulla or brain. We show that adrenal gland size is increased in NF1Prx1 mice. Nf1Prx1 female mice showed corticosterone and aldosterone overproduction. Molecular analysis of Nf1 deficient adrenals revealed deregulation of multiple proteins, including steroidogenic acute regulatory protein (StAR), a vital mitochondrial factor promoting transfer of cholesterol into steroid making mitochondria. This was associated with a marked upregulation of MAPK pathway and a female specific increase of cAMP concentration in murine adrenal lysates. Complementarily, we characterized a patient with neurofibromatosis type I with macronodular adrenal hyperplasia with ACTH-independent cortisol overproduction. Comparison of normal control tissue- and adrenal hyperplasia- derived genomic DNA revealed loss of heterozygosity (LOH) of the wild type NF1 allele, showing that biallelic NF1 gene inactivation occurred in the hyperplastic adrenal gland. Conclusions Our data suggest that biallelic loss of Nf1 induces autonomous adrenal hyper-activity. We conclude that Nf1 is involved in the regulation of adrenal cortex function in mice and humans. PMID:25775093

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

PubMed

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

2017-05-01

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

Birthmarks - pigmented

MedlinePlus

Hairy nevus; Nevi; Mole; Cafe-au-lait spots; Congenital nevus ... Different types of birthmarks have different causes. Cafe-au-lait spots are common at or after birth. Someone who has many of these spots may have a genetic disorder called neurofibromatosis . ...

Background Model for the Majorana Demonstrator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cuesta, C.; Abgrall, N.; Aguayo, Estanislao

2015-06-01

The Majorana Collaboration is constructing a prototype system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment to search for neutrinoless double-beta (0v BB) decay in 76Ge. In view of the requirement that the next generation of tonne-scale Ge-based 0vBB-decay experiment be capable of probing the neutrino mass scale in the inverted-hierarchy region, a major goal of theMajorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursuedmore » through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using Geant4 simulations of the different background components whose purity levels are constrained from radioassay measurements.« less

Cephalopod dynamic camouflage: bridging the continuum between background matching and disruptive coloration

PubMed Central

Hanlon, R.T.; Chiao, C.-C.; Mäthger, L.M.; Barbosa, A.; Buresch, K.C.; Chubb, C.

2008-01-01

Individual cuttlefish, octopus and squid have the versatile capability to use body patterns for background matching and disruptive coloration. We define—qualitatively and quantitatively—the chief characteristics of the three major body pattern types used for camouflage by cephalopods: uniform and mottle patterns for background matching, and disruptive patterns that primarily enhance disruptiveness but aid background matching as well. There is great variation within each of the three body pattern types, but by defining their chief characteristics we lay the groundwork to test camouflage concepts by correlating background statistics with those of the body pattern. We describe at least three ways in which background matching can be achieved in cephalopods. Disruptive patterns in cuttlefish possess all four of the basic components of ‘disruptiveness’, supporting Cott's hypotheses, and we provide field examples of disruptive coloration in which the body pattern contrast exceeds that of the immediate surrounds. Based upon laboratory testing as well as thousands of images of camouflaged cephalopods in the field (a sample is provided on a web archive), we note that size, contrast and edges of background objects are key visual cues that guide cephalopod camouflage patterning. Mottle and disruptive patterns are frequently mixed, suggesting that background matching and disruptive mechanisms are often used in the same pattern. PMID:19008200

Evaluation of a Method Using Three Genomic Guided Escherichia coli Markers for Phylogenetic Typing of E. coli Isolates of Various Genetic Backgrounds.

PubMed

Hamamoto, Kouta; Ueda, Shuhei; Yamamoto, Yoshimasa; Hirai, Itaru

2015-06-01

Genotyping and characterization of bacterial isolates are essential steps in the identification and control of antibiotic-resistant bacterial infections. Recently, one novel genotyping method using three genomic guided Escherichia coli markers (GIG-EM), dinG, tonB, and dipeptide permease (DPP), was reported. Because GIG-EM has not been fully evaluated using clinical isolates, we assessed this typing method with 72 E. coli collection of reference (ECOR) environmental E. coli reference strains and 63 E. coli isolates of various genetic backgrounds. In this study, we designated 768 bp of dinG, 745 bp of tonB, and 655 bp of DPP target sequences for use in the typing method. Concatenations of the processed marker sequences were used to draw GIG-EM phylogenetic trees. E. coli isolates with identical sequence types as identified by the conventional multilocus sequence typing (MLST) method were localized to the same branch of the GIG-EM phylogenetic tree. Sixteen clinical E. coli isolates were utilized as test isolates without prior characterization by conventional MLST and phylogenetic grouping before GIG-EM typing. Of these, 14 clinical isolates were assigned to a branch including only isolates of a pandemic clone, E. coli B2-ST131-O25b, and these results were confirmed by conventional typing methods. Our results suggested that the GIG-EM typing method and its application to phylogenetic trees might be useful tools for the molecular characterization and determination of the genetic relationships among E. coli isolates. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Genetic predisposition to peripheral nerve neoplasia: Diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes

PubMed Central

Rodriguez, Fausto J.; Stratakis, Constantine A.; Evans, D Gareth

2013-01-01

Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately a third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney Complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia. PMID:22210082

Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes.

PubMed

Rodriguez, Fausto J; Stratakis, Constantine A; Evans, D Gareth

2012-03-01

Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system, and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately one-third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET, respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia.

Strain Background Modifies Phenotypes in the ATP8B1-Deficient Mouse

PubMed Central

Vargas, Julie C.; Xu, Hongmei; Groen, Annamiek; Paulusma, Coen C.; Grenert, James P.; Pawlikowska, Ludmila; Sen, Saunak; Elferink, Ronald P. J. Oude; Bull, Laura N.

2010-01-01

Background Mutations in ATP8B1 (FIC1) underlie cases of cholestatic disease, ranging from chronic and progressive (progressive familial intrahepatic cholestasis) to intermittent (benign recurrent intrahepatic cholestasis). The ATP8B1-deficient mouse serves as an animal model of human ATP8B1 deficiency. Methodology/Principal Findings We investigated the effect of genetic background on phenotypes of ATP8B1-deficient and wild-type mice, using C57Bl/6 (B6), 129, and (B6-129) F1 strain backgrounds. B6 background resulted in greater abnormalities in ATP8B1-deficient mice than did 129 and/or F1 background. ATP8B1-deficient pups of B6 background gained less weight. In adult ATP8B1-deficient mice at baseline, those of B6 background had lower serum cholesterol levels, higher serum alkaline phosphatase levels, and larger livers. After challenge with cholate-supplemented diet, these mice exhibited higher serum alkaline phosphatase and bilirubin levels, greater weight loss and larger livers. ATP8B1-deficient phenotypes in mice of F1 and 129 backgrounds are usually similar, suggesting that susceptibility to manifestations of ATP8B1 deficiency may be recessive. We also detected differences in hepatobiliary phenotypes between wild-type mice of differing strains. Conclusions/Significance Our results indicate that the ATP8B1-deficient mouse in a B6 background may be a better model of human ATP8B1 deficiency and highlight the importance of informed background strain selection for mouse models of liver disease. PMID:20126555

Children's Mental Health: Problems and Services. Background Paper.

ERIC Educational Resources Information Center

Congress of the U.S., Washington, DC. Office of Technology Assessment.

This background paper on children's mental health indicates that less than one-third of the children who have mental health problems receive treatment. Types of mental health problems are discussed, including intellectual, developmental, behavior, emotional, psychophysiological, and adjustment disorders. Enviromental risk factors of poverty and…

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 nonsensemore » 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.« less

Neurocutaneous Disorders.

PubMed

Rosser, Tena

2018-02-01

This article presents an up-to-date summary of the genetic etiology, diagnostic criteria, clinical features, and current management recommendations for the most common neurocutaneous disorders encountered in clinical adult and pediatric neurology practices. The phakomatoses are a phenotypically and genetically diverse group of multisystem disorders that primarily affect the skin and central nervous system. A greater understanding of the genetic and biological underpinnings of numerous neurocutaneous disorders has led to better clinical characterization, more refined diagnostic criteria, and improved treatments in neurofibromatosis type 1, Legius syndrome, neurofibromatosis type 2, Noonan syndrome with multiple lentigines, tuberous sclerosis complex, Sturge-Weber syndrome, and incontinentia pigmenti. Neurologists require a basic knowledge of and familiarity with a wide variety of neurocutaneous disorders because of the frequent involvement of the central and peripheral nervous systems. A simple routine skin examination can often open a broad differential diagnosis and lead to improved patient care.

[Composite pheochromocytoma: A rare adrenal tumor].

PubMed

Robinet, Gwladys; Rioux-Leclercq, Nathalie; Manunta, Andréa; Mathieu, Romain; Tissier, Frédérique; Peyronnet, Benoit; Kammerer-Jacquet, Solène-Florence

2017-04-01

Composite pheochromocytoma is a rare tumor of the adrenal medulla composed of pheochromocytoma and neuroblastic tumor. We report the case of a composite pheochromocytoma detected in a patient with neurofibromatosis type 1. A 61-year-old male patient presented occasional sweats with palpitation and moderate high blood pressure. Urinary catecholamine level was increased. CT scan showed a heterogeneous tumor limited to the adrenal gland. Histologically, the tumor showed two components: pheochromocytoma and ganglioneuroma and was diagnosed as a composite pheochromocytoma. This tumor is particularly associated with neurofibromatosis type 1, the NF1 germline gene mutation may be involved in its physiopathology. Composite pheochromocytoma is a rare tumor whose pheochromocytoma component is suspected clinically but the final diagnosis is assessed by pathological examination. Prognosis is still difficult to establish due to the rarity of these tumors. Copyright © 2016 Elsevier Masson SAS. All rights reserved.