Neurofibromatosis Type 1
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Neurofibromatosis Type 2 (NF2)
International Journal of Molecular Sciences Review Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis Suha Bachir 1,† , Sanjit Shah 2,† , Scott Shapiro 3,†, Abigail Koehler 4, Abdelkader Mahammedi 5 , Ravi N. Samy 3, Mario Zuccarello 2, Elizabeth Schorry 1 and Soma Sengupta 4,* 1 Department of Genetics, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA; [email protected] (S.B.); [email protected] (E.S.) 2 Department of Neurosurgery, University of Cincinnati, Cincinnati, OH 45267, USA; [email protected] (S.S.); [email protected] (M.Z.) 3 Department of Otolaryngology, University of Cincinnati, Cincinnati, OH 45267, USA; [email protected] (S.S.); [email protected] (R.N.S.) 4 Department of Neurology, University of Cincinnati, Cincinnati, OH 45267, USA; [email protected] 5 Department of Radiology, University of Cincinnati, Cincinnati, OH 45267, USA; [email protected] * Correspondence: [email protected] † These authors contributed equally. Abstract: Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. -
Risk Factors for Gliomas and Meningiomas in Males in Los Angeles County1
[CANCER RESEARCH 49, 6137-6143. November 1, 1989] Risk Factors for Gliomas and Meningiomas in Males in Los Angeles County1 Susan Preston-Martin,2 Wendy Mack, and Brian E. Henderson Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California 90033 ABSTRACT views with proxy respondents, we were unable to include a large proportion of otherwise eligible cases because they were deceased or Detailed job histories and information about other suspected risk were too ill or impaired to participate in an interview. The Los Angeles factors were obtained during interviews with 272 men aged 25-69 with a County Cancer Surveillance Program identified the cases (26). All primary brain tumor first diagnosed during 1980-1984 and with 272 diagnoses had been microscopically confirmed. individually matched neighbor controls. Separate analyses were con A total of 478 patients were identified. The hospital and attending ducted for the 202 glioma pairs and the 70 meningioma pairs. Meningi- physician granted us permission to contact 396 (83%) patients. We oma, but not glioma, was related to having a serious head injury 20 or were unable to locate 22 patients, 38 chose not to participate, and 60 more years before diagnosis (odds ratio (OR) = 2.3; 95% confidence were aphasie or too ill to complete the interview. We interviewed 277 interval (CI) = 1.1-5.4), and a clear dose-response effect was observed patients (74% of the 374 patients contacted about the study or 58% of relating meningioma risk to number of serious head injuries (/' for trend the initial 478 patients). -
Information About Mosaic Neurofibromatosis Type 2 (NF2)
Information about mosaic Neurofibromatosis type 2 (NF2) NF2 occurs because of a mutation (change) in the NF2 gene. When this change is present at the time of conception the changed gene will be present in all the cells of the baby. When this mutation occurs later in the development of the forming embryo, the baby will go on to have a mix of cells: some with the “normal” genetic information and some with the changed information. This mix of cells is called mosaicism. Approximately half the people who have a diagnosis of NF2 have inherited the misprinted NF2 gene change from their mother or father who will also have NF2. They will have that misprinted gene in all the cells of their body. When they have their children, there will be a 1 in 2 chance of passing on NF2 to each child they have. However about half of people with NF2 are the first person in the family to be affected. They have no family history and have not inherited the condition from a parent. When doctors studied this group of patients more closely they noticed certain characteristics. Significantly they observed that fewer children had inherited NF2 than expected some people in this group had relatively mild NF2 NF2 tumours in some patients tended to grow on one side of their body rather than both sides that when a blood sample was tested to identify the NF2 gene, the gene change could not be found in 30-40% of people This lead researchers to conclude that this group of people were most likely to be mosaic for NF2 i.e. -
Central Nervous System Tumors General ~1% of Tumors in Adults, but ~25% of Malignancies in Children (Only 2Nd to Leukemia)
Last updated: 3/4/2021 Prepared by Kurt Schaberg Central Nervous System Tumors General ~1% of tumors in adults, but ~25% of malignancies in children (only 2nd to leukemia). Significant increase in incidence in primary brain tumors in elderly. Metastases to the brain far outnumber primary CNS tumors→ multiple cerebral tumors. One can develop a very good DDX by just location, age, and imaging. Differential Diagnosis by clinical information: Location Pediatric/Young Adult Older Adult Cerebral/ Ganglioglioma, DNET, PXA, Glioblastoma Multiforme (GBM) Supratentorial Ependymoma, AT/RT Infiltrating Astrocytoma (grades II-III), CNS Embryonal Neoplasms Oligodendroglioma, Metastases, Lymphoma, Infection Cerebellar/ PA, Medulloblastoma, Ependymoma, Metastases, Hemangioblastoma, Infratentorial/ Choroid plexus papilloma, AT/RT Choroid plexus papilloma, Subependymoma Fourth ventricle Brainstem PA, DMG Astrocytoma, Glioblastoma, DMG, Metastases Spinal cord Ependymoma, PA, DMG, MPE, Drop Ependymoma, Astrocytoma, DMG, MPE (filum), (intramedullary) metastases Paraganglioma (filum), Spinal cord Meningioma, Schwannoma, Schwannoma, Meningioma, (extramedullary) Metastases, Melanocytoma/melanoma Melanocytoma/melanoma, MPNST Spinal cord Bone tumor, Meningioma, Abscess, Herniated disk, Lymphoma, Abscess, (extradural) Vascular malformation, Metastases, Extra-axial/Dural/ Leukemia/lymphoma, Ewing Sarcoma, Meningioma, SFT, Metastases, Lymphoma, Leptomeningeal Rhabdomyosarcoma, Disseminated medulloblastoma, DLGNT, Sellar/infundibular Pituitary adenoma, Pituitary adenoma, -
Adrenal Neuroblastoma Mimicking Pheochromocytoma in an Adult With
Khalayleh et al. Int Arch Endocrinol Clin Res 2017, 3:008 Volume 3 | Issue 1 International Archives of Endocrinology Clinical Research Case Report : Open Access Adrenal Neuroblastoma Mimicking Pheochromocytoma in an Adult with Neurofibromatosis Type 1 Harbi Khalayleh1, Hilla Knobler2, Vitaly Medvedovsky2, Edit Feldberg3, Judith Diment3, Lena Pinkas4, Guennadi Kouniavsky1 and Taiba Zornitzki2* 1Department of Surgery, Hebrew University Medical School of Jerusalem, Israel 2Endocrinology, Diabetes and Metabolism Institute, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Israel 3Pathology Institute, Kaplan Medical Center, Israel 4Nuclear Medicine Institute, Kaplan Medical Center, Israel *Corresponding author: Taiba Zornitzki, MD, Endocrinology, Diabetes and Metabolism Institute, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 1, 76100 Rehovot, Israel, Tel: +972-894- 41315, Fax: +972-8 944-1912, E-mail: [email protected] Context 2. This is the first reported case of an adrenal neuroblastoma occurring in an adult patient with NF1 presenting as a large Neurofibromatosis type 1 (NF1) is a genetic disorder asso- adrenal mass with increased catecholamine levels mimicking ciated with an increased risk of malignant disorders. Adrenal a pheochromocytoma. neuroblastoma is considered an extremely rare tumor in adults and was not previously described in association with NF1. 3. This case demonstrates the clinical overlap between pheo- Case description: A 42-year-old normotensive woman with chromocytoma and neuroblastoma. typical signs of NF1 underwent evaluation for abdominal pain, Keywords and a large 14 × 10 × 16 cm left adrenal mass displacing the Adrenal neuroblastoma, Neurofibromatosis type 1, Pheo- spleen, pancreas and colon was found. An initial diagnosis of chromocytoma, Neural crest-derived tumors pheochromocytoma was done based on the known strong association between pheochromocytoma, NF1 and increased catecholamine levels. -
A Case of Intramedullary Spinal Cord Astrocytoma Associated with Neurofibromatosis Type 1
KISEP J Korean Neurosurg Soc 36 : 69-71, 2004 Case Report A Case of Intramedullary Spinal Cord Astrocytoma Associated with Neurofibromatosis Type 1 Jae Taek Hong, M.D.,1 Sang Won Lee, M.D.,1 Byung Chul Son, M.D.,1 Moon Chan Kim, M.D.2 Department of Neurosurgery,1 St. Vincent Hospital, The Catholic University of Korea, Suwon, Korea Department of Neurosurgery,2 Kangnam St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea The authors report a symptomatic intramedullary spinal cord astrocytoma in the thoracolumbar area associated with neurofibromatosis type 1 (NF-1). A 38-year-old woman presented with paraparesis. Magnetic resonance imaging revealed an intramedullary lesion within the lower thoracic spinal cord and conus medullaris, which was removed surgically. Pathological investigation showed anaplastic astrocytoma. This case confirms that the diagnosis criteria set by the National Institute of Health Consensus Development Conference can be useful to differentiate ependymoma from astrocytoma when making a preoperative diagnosis of intramedullary spinal cord tumor in patients of NF-1. KEY WORDS : Astrocytoma·Intramedullary cord tumor·Neurofibromatosis. Introduction eurofibromatosis type 1 (NF-1), also known as von N Recklinghausen's disease, is one of the most common autosomal dominant inherited disorders with an incidence of 1 in 3,000 individuals and is characterized by a predisposition to tumors of the nervous system5,6,12,16). Central nervous system lesions associated with NF-1 include optic nerve glioma and low-grade gliomas of the hypothalamus, cerebellum and brain stem6,10). Since the introduction of magnetic resonance(MR) imaging, Fig. 1. Photograph of the patient's back shows multiple subcutaneous incidental lesions with uncertain pathological characteristic nodules (black arrow) and a cafe-au-lait spot (white arrow), which have been a frequent finding in the brain and spinal cord of are typical of NF-1. -
Survival and Functional Outcome of Childhood Spinal Cord Low-Grade Gliomas
J Neurosurg Pediatrics 4:000–000,254–261, 2009 Survival and functional outcome of childhood spinal cord low-grade gliomas Clinical article KATRIN SCHEINEMANN, M.D.,1 UTE BARTELS, M.D.,2 ANNIE HUANG, M.D., PH.D.,2 CYNTHIA HAWKINS, M.D., PH.D.,3 ABHAYA V. KULKARNI, M.D., PH.D.,4 ERIC BOUFFET, M.D.,2 AND URI TABORI, M.D.2 1Division of Hematology/Oncology, McMaster Children’s Hospital, Hamilton; and Divisions of 2Hematology/ Oncology, 3Pathology, and 4Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada Object. Intramedullary spinal cord low-grade gliomas (LGGs) are rare CNS neoplasms in pediatric patients, and there is little information on therapy for and outcome of these tumors in this population. Furthermore, most patient series combine adult and pediatric patients or high- and low-grade tumors, resulting in controversial data regarding optimal treatment of these children. To clarify these issues, the authors performed a regional population-based study of spinal cord LGGs in pediatric patients. Methods.$OOSHGLDWULFSDWLHQWVZLWK/**VWUHDWHGGXULQJWKH05LPDJLQJHUD ² ZHUHLGHQWLÀHGLQ the comprehensive database of the Hospital for Sick Children in Toronto. Data on demographics, pathology, treat- ment details, and outcomes were collected. Results. Spinal cord LGGs in pediatric patients constituted 29 (4.6%) of 635 LGGs. Epidemiological and clini- cal data in this cohort were different than in patients with other spinal tumors and strikingly similar to data from pediatric patients with intracranial LGGs. The authors observed an age peak at 2 years and a male predominance in patients with these tumors. Histological testing revealed a Grade I astrocytoma in 86% of tumors. -
MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature
J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] Abstract The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. -
Cutaneous Neurofibromas: Clinical Definitions Current Treatment Is Limited to Surgical Removal Or Physical Or Descriptors Destruction
ARTICLE OPEN ACCESS Cutaneous neurofibromas Current clinical and pathologic issues Nicolas Ortonne, MD, PhD,* Pierre Wolkenstein, MD, PhD,* Jaishri O. Blakeley, MD, Bruce Korf, MD, PhD, Correspondence Scott R. Plotkin, MD, PhD, Vincent M. Riccardi, MD, MBA, Douglas C. Miller, MD, PhD, Susan Huson, MD, Dr. Wolkenstein Juha Peltonen, MD, PhD, Andrew Rosenberg, MD, Steven L. Carroll, MD, PhD, Sharad K. Verma, PhD, [email protected] Victor Mautner, MD, Meena Upadhyaya, PhD, and Anat Stemmer-Rachamimov, MD Neurology® 2018;91 (Suppl 1):S5-S13. doi:10.1212/WNL.0000000000005792 Abstract RELATED ARTICLES Objective Creating a comprehensive To present the current terminology and natural history of neurofibromatosis 1 (NF1) cuta- research strategy for neous neurofibromas (cNF). cutaneous neurofibromas Page S1 Methods NF1 experts from various research and clinical backgrounds reviewed the terms currently in use The biology of cutaneous fi for cNF as well as the clinical, histologic, and radiographic features of these tumors using neuro bromas: Consensus published and unpublished data. recommendations for setting research priorities Results Page S14 Neurofibromas develop within nerves, soft tissue, and skin. The primary distinction between fi fi Considerations for cNF and other neuro bromas is that cNF are limited to the skin whereas other neuro bromas development of therapies may involve the skin, but are not limited to the skin. There are important cellular, molecular, for cutaneous histologic, and clinical features of cNF. Each of these factors is discussed in consideration of neurofibroma a clinicopathologic framework for cNF. Page S21 Conclusion Clinical trial design for The development of effective therapies for cNF requires formulation of diagnostic criteria that cutaneous neurofibromas encompass the clinical and histologic features of these tumors. -
Risk-Adapted Therapy for Young Children with Embryonal Brain Tumors, High-Grade Glioma, Choroid Plexus Carcinoma Or Ependymoma (Sjyc07)
SJCRH SJYC07 CTG# - NCT00602667 Initial version, dated: 7/25/2007, Resubmitted to CPSRMC 9/24/2007 and 10/6/2007 (IRB Approved: 11/09/2007) Activation Date: 11/27/2007 Amendment 1.0 dated January 23, 2008, submitted to CPSRMC: January 23, 2008, IRB Approval: March 10, 2008 Amendment 2.0 dated April 16, 2008, submitted to CPSRMC: April 16, 2008, (IRB Approval: May 13, 2008) Revision 2.1 dated April 29, 2009 (IRB Approved: April 30, 2009 ) Amendment 3.0 dated June 22, 2009, submitted to CPSRMC: June 22, 2009 (IRB Approved: July 14, 2009) Activated: August 11, 2009 Amendment 4.0 dated March 01, 2010 (IRB Approved: April 20, 2010) Activated: May 3, 2010 Amendment 5.0 dated July 19, 2010 (IRB Approved: Sept 17, 2010) Activated: September 24, 2010 Amendment 6.0 dated August 27, 2012 (IRB approved: September 24, 2012) Activated: October 18, 2012 Amendment 7.0 dated February 22, 2013 (IRB approved: March 13, 2013) Activated: April 4, 2013 Amendment 8.0 dated March 20, 2014. Resubmitted to IRB May 20, 2014 (IRB approved: May 22, 2014) Activated: May 30, 2014 Amendment 9.0 dated August 26, 2014. (IRB approved: October 14, 2014) Activated: November 4, 2014 Un-numbered revision dated March 22, 2018. (IRB approved: March 27, 2018) Un-numbered revision dated October 22, 2018 (IRB approved: 10-24-2018) RISK-ADAPTED THERAPY FOR YOUNG CHILDREN WITH EMBRYONAL BRAIN TUMORS, HIGH-GRADE GLIOMA, CHOROID PLEXUS CARCINOMA OR EPENDYMOMA (SJYC07) Principal Investigator Amar Gajjar, M.D. Division of Neuro-Oncology Department of Oncology Section Coordinators David Ellison, M.D., Ph.D. -
Astrocytoma: a Hormone-Sensitive Tumor?
International Journal of Molecular Sciences Review Astrocytoma: A Hormone-Sensitive Tumor? Alex Hirtz 1, Fabien Rech 1,2,Hélène Dubois-Pot-Schneider 1 and Hélène Dumond 1,* 1 Université de Lorraine, CNRS, CRAN, F-54000 Nancy, France; [email protected] (A.H.); [email protected] (F.R.); [email protected] (H.D.-P.-S.) 2 Université de Lorraine, CHRU-Nancy, Service de Neurochirurgie, F-54000 Nancy, France * Correspondence: [email protected]; Tel.: +33-372746115 Received: 29 October 2020; Accepted: 27 November 2020; Published: 30 November 2020 Abstract: Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women’s brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas. -
An Unusual Case of Cowden Syndrome Associated With
Pistorius et al. Hereditary Cancer in Clinical Practice (2016) 14:11 DOI 10.1186/s13053-016-0051-8 CASE REPORT Open Access An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis Steffen Pistorius1,6*†, Barbara Klink2,7*†, Jessica Pablik3, Andreas Rump2, Daniela Aust3,7, Marlene Garzarolli4, Evelin Schröck2,7 and Hans K. Schackert5,6,7 Abstract Background: Ganglioneuromatous polyposis (GP) is a very rare disorder which may be associated with other clinical manifestations and syndromes, such as Cowden syndrome, multiple endocrine neoplasia (MEN) type II and neurofibromatosis (NF) 1. The risk for malignant transformation of ganglioneuromas is unknown, and the combination of GP with colon cancer has been only very seldom reported. Methods and results: We report the case of a 60-year old male patient with adenocarcinoma, adenomas and lipomas of the colon and multiple gastroduodenal lesions combined with generalised lipomatosis and macrocephaly. Based on the initial endoscopic and histological findings, a (restorative) proctocolectomy was recommended but declined by the patient. Instead, a colectomy was performed. The histological examination revealed an unforeseen GP in addition to the colon cancer. Extensive molecular diagnostics allowed for the differential diagnosis of the causes of the clinical manifestations, and the clinical suspicion of Cowden syndrome could not be confirmed using Sanger Sequencing and MLPA for the analysis of PTEN. Finally, a pathogenic germline mutation in PTEN (heterozygous stop mutation in exon 2: NM_000314 (PTEN):c.138C > A; p.Tyr46*) could be detected by next-generation sequencing (NGS), confirming an unusual presentation of Cowden syndrome with GP. Conclusions: Cowden syndrome should be considered in cases of GP with extracolonic manifestation and verified by combined clinical and molecular diagnostics.