DOCSLIB.ORG

Parkes Weber Syndrome, Vein of Galen Aneurysmal Malformation, and Other Fast-Flow Vascular Anomalies Are Caused by RASA1 Mutations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Parkes Weber Syndrome, Vein of Galen Aneurysmal Malformation, and Other Fast-Flow Vascular Anomalies Are Caused by RASA1 Mutations Revencu, N; Boon, L M; Mulliken, J B; Enjolras, O; Cordisco, M R; Burrows, P E; Clapuyt, P; Hammer, F; Dubois, J; Baselga, E; Brancati, F; Carder, R; Quintal, J M C; Dallapiccola, B; Fischer, G; Frieden, I J; Garzon, M; Harper, J; Johnson-Patel, J; Labrèze, C; Martorell, L; Paltiel, H J; Pohl, A; Prendiville, J; Quere, I; Siegel, D H; Valente, E M; Van Hagen, A; Van Hest, L; Vaux, K K; Vicente, A; Weibel, L; Chitayat, D; Vikkula, M (2008). Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Human Mutation, 29(7):959-965. University of Zurich Postprint available at: Zurich Open Repository and Archive http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Winterthurerstr. 190 CH-8057 Zurich Originally published at: http://www.zora.uzh.ch Human Mutation 2008, 29(7):959-965. Year: 2008 Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations Revencu, N; Boon, L M; Mulliken, J B; Enjolras, O; Cordisco, M R; Burrows, P E; Clapuyt, P; Hammer, F; Dubois, J; Baselga, E; Brancati, F; Carder, R; Quintal, J M C; Dallapiccola, B; Fischer, G; Frieden, I J; Garzon, M; Harper, J; Johnson-Patel, J; Labrèze, C; Martorell, L; Paltiel, H J; Pohl, A; Prendiville, J; Quere, I; Siegel, D H; Valente, E M; Van Hagen, A; Van Hest, L; Vaux, K K; Vicente, A; Weibel, L; Chitayat, D; Vikkula, M Revencu, N; Boon, L M; Mulliken, J B; Enjolras, O; Cordisco, M R; Burrows, P E; Clapuyt, P; Hammer, F; Dubois, J; Baselga, E; Brancati, F; Carder, R; Quintal, J M C; Dallapiccola, B; Fischer, G; Frieden, I J; Garzon, M; Harper, J; Johnson-Patel, J; Labrèze, C; Martorell, L; Paltiel, H J; Pohl, A; Prendiville, J; Quere, I; Siegel, D H; Valente, E M; Van Hagen, A; Van Hest, L; Vaux, K K; Vicente, A; Weibel, L; Chitayat, D; Vikkula, M (2008). Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Human Mutation, 29(7):959-965. Postprint available at: http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Originally published at: Human Mutation 2008, 29(7):959-965. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations Abstract Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one-third had fast-flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast-flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM-AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity. Parkes Weber syndrome and other fast-flow vascular lesions associate with CM-AVM and RASA1 mutations N. Revencu1,2, L.M. Boon1,3, J.B. Mulliken4, O. Enjolras5, M.R. Cordisco6, P.E. Burrows4, Ph Clapuyt7, F. Hammer7, J. Dubois8, E. Baselga9, F.Brancati10, B. Dallapiccola10, R. Carder11, G. Fischer12, I. Frieden13, J Harper14, P. Gritters15, J Johnson Patel16, C. Labrèze17, L. Martorell18, H. J. Paltiel4, A. Pohl19, J. Prendiville20, I. Quere21, D.H. Siegel13, E.M. Valente10, Vaux K16, L. Weibel14, J.M. Ceballos Quintal22, D. Chitayat23 and M. Vikkula1 1Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, Belgium; 2 Center for Human Genetics, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium; 3Vascular Anomalies Centre, Division of Plastic Surgery, Cliniques universitaires St Luc, Brussels, Belgium; 4Vascular Anomalies Center, Division of Plastic Surgery and Department of Radiology, Children's Hospital, Harvard Medical School, Boston, MA, USA; 5Consultation des Angiomes, Lariboisière Hospital, Paris, France; 6Hospital nacional de Pediatria, Argentina; 7Department of Radiology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; 8Department of Medical Imaging, Sainte-Justine Mother-Child University Hospital, Montreal, Canada; 9Hospital de la Sant Pau, Barcelona, Spain; 10Mendel Institute, Rome, Italy; 11Southwestern Medical Center, Dallas, USA; 12Royal North Shore Hospital, St Leonards, Australia; 13University of California School of Medicine, San Francisco, California, USA; 14Department of Pediatric Dermatology, Great Ormond Street Hospital for Children, London, UK; 15VU Medical Center, Amsterdam, Netherlands; 16Medical Genetics, University of California San Diego, USA; 17Hôpital Pellegrin Enfants, Bordeaux, France; 18Genetica Molecular, Hospital Sant Joan de Déu, Barcelona, Spain; 19Zentrum fur Kinderheilkunde und Jugendmedizin, Freiburg, Germany; 20Division of Pediatric Dermatology, Department of Pediatrics, University of British Columbia, British Columbia Children's Hospital, Vancouver, Canada; 21Centre Hospitalier Universitaire, Montpellier, France; 22Laboratorio de Genetica, Yucatan, Mexico; 23Mount Sinai Hospital, Toronto, Canada ABSTRACT Background Mutations in RASA1 have been documented in 6 families (39 individuals) with autosomal dominant multifocal capillary malformations (CMs). Nine individuals had an associated arteriovenous malformation/fistula (AVM/AVF). One patient had Parkes Weber syndrome, a disorder considered to be sporadic and non-genetic. We investigated the RASA1 involvement in a large series of patients with CM and fast-flow vascular lesions. Methods We collected clinical information and DNA samples for 61 probands and their families with a phenotype similar to that observed in the original study: 56 had multifocal CMs, and 35 also had a fast-flow anomaly: 16 Parkes Weber syndrome and 19 either an AVM or an AVF; 5 had Parkes Weber syndrome without multifocal CMs. RASA1 was screened by DHPLC followed by sequencing. Results We identified 42 distinct mutations in 44/61 probands: 13/16 with Parkes Weber syndrome, 16/19 with AVM/AVF, 15/21 with multifocal CMs only, and 0/5 with Parkes Weber syndrome without multifocal CMs. Fifty-seven relatives also had a RASA1 mutation. Overall, 17 individuals with RASA1 mutations had an AVM/AVF: 8 intracerebral, 2 of which were vein of Galen aneurysmal malformations. In addition, several CMs demonstrated fast-flow on hand-held Doppler. Moreover, 6 patients had either benign or malignant tumors, 3 of which are known to occur in neurofibromatosis. Penetrance was 98% and de novo occurrence was 32%. Conclusions Multifocal CM is the hallmark of RASA1 mutation. These patients often have extra- or intracerebral AVM/AVFs, confirming the original association designated capillary malformation- arteriovenous malformation (CM-AVM). In addition, Parkes Weber syndrome with multifocal CMs is a genetic disease, part of CM-AVM spectrum. Furthermore, specific neural tumors may also be linked to RASA1. INTRODUCTION Recognition of the association Capillary Malformation-ArterioVenous Malformation (CM- AVM; OMIM 608354) was the culmination of the research for a gene responsible for inherited capillary stains. Several affected families guided linkage studies and led to the identification of germline mutations in the RASA1 gene in 6 families (39 individuals) 1, 2. These capillary malformations (CMs) were noted to be atypical in what they were multifocal, small, round-to-oval, pinkish-to-red, and randomly distributed. Interestingly, 9/35 affected individuals had either an arteriovenous malformation (AVM) or an arteriovenous fistula (AVF): 2 in the central nervous system and 7 elsewhere (Table 1). The high frequency of fast-flow vascular malformations raised the concern about their possible presence in asymptomatic patients with harmless cutaneous capillary stains. As the latter occur with a birth prevalence of 0.3%, it is important to recognize those patients who have an elevated risk for cutaneous or visceral fast-flow lesions. AVMs are the most difficult-to-treat vascular anomalies in any location, and intracerebral lesions can cause hemorrhagic stroke, hydrocephalus or cognitive impairment. One of the affected family members in the original study (Table 1) was diagnosed as having Parkes Weber syndrome (OMIM 608355), a fast-flow vascular disorder characterized by a cutaneous vascular stain with multiple arteriovenous fistulas and overgrowth of the affected extremity 3. This condition, described in 1918 by Parkes Weber 4, has always been considered to be one of the sporadic overgrowth syndromes. Most of these are of unknown etiology, although they have been hypothesized to be non-genetic or caused by somatic mosaicism. The phenotypic similarity among these disorders often leads to misdiagnosis
Load more

Recommended publications
  • Segmental Overvekst Og Vaskulærmalformasjoner V02
    2/1/2021 Segmental overvekst og vaskulærmalformasjoner v02 Avdeling for medisinsk genetikk Segmental overvekst og vaskulærmalformasjoner Genpanel, versjon v02 * Enkelte genomiske regioner har lav eller ingen sekvensdekning ved eksomsekvensering. Dette skyldes at de har stor likhet med andre områder i genomet, slik at spesifikk gjenkjennelse av disse områdene og påvisning av varianter i disse områdene, blir vanskelig og upålitelig. Disse genetiske regionene har vi identifisert ved å benytte USCS segmental duplication hvor områder større enn 1 kb og ≥90% likhet med andre regioner i genomet, gjenkjennes (https://genome.ucsc.edu). Vi gjør oppmerksom på at ved identifiseringav ekson oppstrøms for startkodon kan eksonnummereringen endres uten at transkript ID endres. Avdelingens websider har en full oversikt over områder som er affisert av segmentale duplikasjoner. ** Transkriptets kodende ekson. Ekson Gen Gen affisert (HGNC (HGNC Transkript Ekson** Fenotype av symbol) ID) segdup* ACVRL1 175 NM_000020.3 2-10 Telangiectasia, hereditary hemorrhagic, type 2 OMIM ADAMTS3 219 NM_014243.3 1-22 Hennekam lymphangiectasia- lymphedema syndrome 3 OMIM AKT1 391 NM_005163.2 2-14 Cowden syndrome 6 OMIM Proteus syndrome, somatic OMIM AKT2 392 NM_001626.6 2-14 Diabetes mellitus, type II OMIM Hypoinsulinemic hypoglycemia with hemihypertrophy OMIM AKT3 393 NM_005465.7 2-14 Megalencephaly-polymicrogyria- polydactyly-hydrocephalus syndrome 2 OMIM file:///data/SegOv_v02-web.html 1/7 2/1/2021 Segmental overvekst og vaskulærmalformasjoner v02 Ekson Gen Gen affisert (HGNC (HGNC
    [Show full text]
  • WES Gene Package Multiple Congenital Anomalie.Xlsx
    Whole Exome Sequencing Gene package Multiple congenital anomalie, version 5, 1‐2‐2018 Technical information DNA was enriched using Agilent SureSelect Clinical Research Exome V2 capture and paired‐end sequenced on the Illumina platform (outsourced). The aim is to obtain 8.1 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA‐MEM algorithm (reference: http://bio‐bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A4GALT [Blood group, P1Pk system, P(2) phenotype], 111400 607922 101 100 100 99 [Blood group, P1Pk system, p phenotype], 111400 NOR polyagglutination syndrome, 111400 AAAS Achalasia‐addisonianism‐alacrimia syndrome, 231550 605378 73 100 100 100 AAGAB Keratoderma, palmoplantar,
    [Show full text]
  • 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.
    [Show full text]
  • Description of the Vanseq Subpanels Offered at Seattle Children’S Hospital
    Description of the VANseq subpanels offered at Seattle Children’s Hospital Capillary Malformations (4 genes): EPHB4, GNA11, GNAQ, RASA1 Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is associated with multiple small (1-2 cm diameter) capillary malformations and is due to loss of function mutations in EPHB4 or RASA1. Approximately 20% of individuals have AVMs, which can be life-threatening. Other features (telangiectasias, lymphedema, non- immune hydrops) have been associated. RASA1 and EPHB4 mutations are also associated with Parkes-Weber syndrome. Somatic activating mutations at codon 183 in the GNAQ gene cause isolated capillary malformations or Sturge Weber Syndrome. Somatic activating mutations at the same residue in GNA11 cause capillary malformation with overgrowth. LM/VM/AVM (17 genes) - Lymphatic Malformations, Venous Malformations, Arteriovenous Malformations: ACVRL1, ARAF, BRAF, ELMO2, ENG, EPHB4, GDF2, GLMN, HRAS, KRAS, MAP2K1, MAP3K3, NRAS, PIK3CA, PTEN, RASA1, TEK (TIE2) Most individuals with isolated lymphatic, venous, or arteriovenous malformations possess somatic, activating mutations in genes associated with cell growth and division. For many of these conditions, sequencing of affected, lesional tissue is required for mutation detection, and coordination with pathology is required. Although there are strong gene-phenotype correlations within this group, there is increasing recognition of phenotypic expansion and overlap. The most commonly mutated gene in this group of conditions is PIK3CA. • ~80% of isolated lymphatic malformations have pathogenic, tissue restricted variant in PIK3CA. • Most venous malformations have activating mutations in TEK (TIE2). TEK mutations can be isolated and somatic or multifocal, inherited in a dominant fashion. • Activating, somatic mutations in MAP2K1 are primarily associated with isolated extracranial AVMs.
    [Show full text]
  • 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.
    [Show full text]
  • Parkes Weber Syndrome Associated with Two Somatic Pathogenic Variants in RASA1
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 8-1-2020 Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1 Josue A. Flores Daboub Johanes F. Grimmer Alice Frigerio Whitney Wooderchak-Donahue Ryan Arnold See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Josue A. Flores Daboub, Johanes F. Grimmer, Alice Frigerio, Whitney Wooderchak-Donahue, Ryan Arnold, Jeff Szymanski, Nicola Longo, and Pinar Bayrak-Toydemir Downloaded from molecularcasestudies.cshlp.org on September 10, 2020 - Published by Cold Spring Harbor Laboratory Press COLD SPRING HARBOR Molecular Case Studies | RESEARCH REPORT Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1 Josue A. Flores Daboub,1 Johanes Fred Grimmer,2 Alice Frigerio,3 Whitney Wooderchak-Donahue,4,5 Ryan Arnold,6 Jeff Szymanski,7 Nicola Longo,1,4 and Pinar Bayrak-Toydemir4,5 1Division of Pediatric Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA; 2Division of Ear, Nose, and Throat, University of Utah, Salt Lake City, Utah 84108, USA; 3Division of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA; 4Department of Pathology, 5ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah 84108, USA; 6Primary Children’s Hospital Interventional Radiology, Salt Lake City, Utah 84113, USA; 7Department of Radiation Oncology, Washington University, St. Louis, Missouri 63130, USA Abstract Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skel- etal components.
    [Show full text]
  • El Paso Community College Syllabus Part II Official Course Description
    DHYG 1239; Revised Fall 2016/Spring 2017 El Paso Community College Syllabus Part II Official Course Description SUBJECT AREA Dental Hygiene COURSE RUBIC AND NUMBER DHYG 1239 COURSE TITLE General and Oral Pathology COURSE CREDIT HOURS 2 2 : 1 Credits Lec Lab I. Catalog Description Offers a general study of disturbances in human body development, diseases of the body, and disease prevention measures with emphasis on the oral cavity and associated structures. A grade of "C" or better is required in this course to take the next course. Prerequisites: BIOL 2401 and BIOL 2402 and CHEM 1306 and 1106. Corequisites: DHYG 1103 and DHYG 1201 and DHYG 1219 and DHYG 1304 and DHYG 1431. (2:1). Lab fee. II. Course Objectives Upon satisfactory completion of the course, the student will be able to: A. Introduction to Preliminary Diagnosis of Oral Lesions 1. Define each of the terms in the vocabulary list for this chapter. 2. List and define the eight diagnostic categories that contribute to the diagnostic process. 3. Name a diagnostic category and give an example of a lesion, anomaly, or condition for which this category contributes greatly to the diagnosis. 4. Describe the clinical appearance of Fordyce=s granules (spots), torus palatinus, mandibular tori, and lingual varicosities, and identify them on a slide. 5. Describe the radiographic picture and historical data (including the age, sex, and race of the patient) that are relevant to periapical cementl dysplasia (cementoma). 6. Define Avariant of normal@ and give three examples of such lesions involving the tongue. 7. List and describe the clinical characteristics and identify a clinical picture of fissured tongue, median rhomboid glossitis, geographic tongue, ectopic geographic tongue, and hairy tongue.
    [Show full text]
  • Cutaneous Findings in Neurofibromatosis Type 1
    cancers Review Cutaneous Findings in Neurofibromatosis Type 1 Bengisu Ozarslan 1 , Teresa Russo 2, Giuseppe Argenziano 2 , Claudia Santoro 3 and Vincenzo Piccolo 2,* 1 Dermatology Unit, Doku Medical Center, 34381 Istanbul, Turkey; [email protected] 2 Dermatology Unit, University of Campania Luigi Vanvitelli, 80100 Naples, Italy; [email protected] (T.R.); [email protected] (G.A.) 3 Department of Woman, Neurofibromatosis Referral Centre, Child and of General and Specialised Surgery, University of Campania Luigi Vanvitelli, 80100 Naples, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-08-1566-6834; Fax: +39-08-1546-8759 Simple Summary: Neurofibromatosis type 1 (NF1) is characterized by major and minor cutaneous findings, whose recognition plays a key role in the early diagnosis of the disease. The disease affects multiple systems and clinical manifestation has a wide range of variability. Symptoms and clinical signs may occur over the lifetime, and the complications are very diverse. Although significant progress has been made in understanding the pathophysiology of the disease, no specific treatment has been defined. Multidisciplinary approach is required to provide optimum care for the patients. The aim of this paper is to provide the clinician with a complete guide of skin findings of NF1. Abstract: Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder associated with germline mutations in the NF1 tumor suppressor gene. NF1 belongs to a class of congenital anomaly syndromes called RASopathies, a group of rare genetic conditions caused by mutations in the Ras/mitogen-activated protein kinase pathway. Generally, NF1 patients present with dermatologic manifestations.
    [Show full text]
  • Genetic Insights Into Cerebrovascular Disorders: a Comprehensive Review
    Genetic Insights into Cerebrovascular Disorders: a Comprehensive Review 1,2 3 4 5 Fawaz Al-Mufti, MD *, Ahmed Alkanaq, MD , Krishna Amuluru, MD , Rolla Nuoman, MD , 6 7 7 Ahmed Abdulrazzaq, DDS , Tamarah Sami, DDS , Halla Nuoaman, MD , Caroline Hayes- 5 2 8 Rosen, MD , Charles J. Prestigiacomo, MD , and Chirag D. Gandhi, MD 1 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, Division of Neuroendovascular Surgery and Neurocritical Care, New Brunswick, New Jersey, USA 2 Rutgers University - New Jersey Medical School, Department of Neurosurgery, Newark, New Jersey, USA 3 Rutgers University - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular 4 University of Pittsburgh Medical Center- Hamot, Department of Neurointerventional Radiology, Erie, Pennsylvania, USA 5 Rutgers University - New Jersey Medical School, Department of Neurology, Division of Child Neurology, Newark, New Jersey, USA 6 Rutgers University - School of Dental Medicine, Newark, New Jersey, USA 7 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, New Brunswick, New Jersey, USA 8 Westchester Medical Center, New York Medical College, Department of Neurosurgery, Valhalla, New York, USA Keywords Cerebrovascular malformations; hereditary diseases Introduction Genetic vascular disorders are usually present at birth; The prevalence of intracranial vascular malformation structurally, they tend to grow proportionately with the has been shown to be increasing over time. This is child, and do not regress spontaneously. The malforma- believed to be due to the advancement in radiological tions vary greatly in number, size, and location, and can procedures. Many studies examining neurological syn- also occur in the context of syndromes.
    [Show full text]
  • Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current Trends in Diagnosis and Management with a Focus on Novel Medical Therapies
    Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current trends in Diagnosis and Management with a focus on Novel Medical Therapies Simone Lisa Ardern-Holmes MBChB, MSc, FRACP A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Health Sciences, The University of Sydney February 2018 1 STATEMENT OF ORIGINALITY This is to certify that this submission is my own work and that, to the best of my knowledge, it contains no material previously published or written by another person, or material which to a substantial extent has been accepted for the award of any other degree or diploma of the university or other institute of higher learning, except where due acknowledgement has been made in the text. Simone L. Ardern-Holmes 2 SUMMARY Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are distinct single gene disorders, which share a predisposition to formation of benign nervous system tumours due to loss of tumour suppressor function. Since identification of the genes encoding NF1 and NF2 in the early 1990s, significant progress has been made in understanding the biological processes and molecular pathways underlying tumour formation. As a result, identifying safe and effective medical approaches to treating NF1 and NF2-associated tumours has become a focus of clinical research and patient care in recent years. This thesis presents a comprehensive discussion of the complications of NF1 and NF2 and approaches to treatment, with a focus on key tumours in each condition. The significant functional impact of these disorders in children and young adults is illustrated, demonstrating the need for coordinated care from experienced multidisciplinary teams.
    [Show full text]
  • Understanding Chronic Venous Disease: a Critical Overview of Its Pathophysiology and Medical Management
    Journal of Clinical Medicine Review Understanding Chronic Venous Disease: A Critical Overview of Its Pathophysiology and Medical Management Miguel A. Ortega 1,2,3,† , Oscar Fraile-Martínez 1,2,† , Cielo García-Montero 1,2,† , Miguel A. Álvarez-Mon 1,2,*, Chen Chaowen 1, Fernando Ruiz-Grande 4,5, Leonel Pekarek 1,2 , Jorge Monserrat 1,2 , Angel Asúnsolo 2,4,6 , Natalio García-Honduvilla 1,2,‡ , Melchor Álvarez-Mon 1,2,7,‡ and Julia Bujan 1,2,‡ 1 Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; [email protected] (M.A.O.); [email protected] (O.F.-M.); [email protected] (C.G.-M.); [email protected] (C.C.); [email protected] (L.P.); [email protected] (J.M.); [email protected] (N.G.-H.); [email protected] (M.Á.-M.); [email protected] (J.B.) 2 Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; [email protected] 3 Cancer Registry and Pathology Department, Hospital Universitario Principe de Asturias, 28806 Alcalá de Henares, Spain 4 Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain; [email protected] 5 Department of Vascular Surgery, Príncipe de Asturias Hospital, 28801 Alcalá de Henares, Spain 6 Department of Epidemiology and Biostatistics, Graduate School of Public Health and Health Policy, The City University of New York, New York, NY 10027, USA 7 Citation: Ortega, M.A.; Immune System Diseases—Rheumatology and Internal Medicine Service, University Hospital Príncipe de Fraile-Martínez, O.; García-Montero, Asturias, (CIBEREHD), 28806 Alcalá de Henares, Spain * Correspondence: [email protected] C.; Álvarez-Mon, M.A.; Chaowen, C.; † These authors contributed equality in this work.
    [Show full text]
  • Blueprint Genetics Noonan Syndrome Panel
    Noonan Syndrome Panel Test code: CA0501 Is a 35 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of a RASopathy including Noonan syndrome with or without lentigines, cardio- facio-cutaneous (CFC) syndrome, Costello syndrome, Noonan-like syndromes or other syndromes causing differential diagnostic challenges such as Legius syndrome, Baraitser-Winter syndromes and neurofibromatosis. About Noonan Syndrome Noonan syndrome is one of the most common syndromes with an estimated prevalence of 1 in 1,000 to 1 in 2,500 live births. It is clinically and genetically heterogeneous condition characterized by cardiovascular abnormalities, distinctive facial features, chest deformity, short stature, and other co-morbidities. Among the Noonan syndrome associated genes, many different genotype-phenotype correlations have been established although no phenotypic features are exclusively associated with one genotype. There are, however, significant differences in the risk of various Noonan syndrome manifestations based on the causative gene. Availability 4 weeks Gene Set Description Genes in the Noonan Syndrome Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACTB* Baraitser-Winter syndrome AD 55 60 ACTG1* Deafness, Baraitser-Winter syndrome AD 27 47 BRAF* LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome AD 134 65 CBL Noonan syndrome-like disorder with or without juvenile myelomonocytic AD 24 43 leukemia CCNK Intellectual disability AD CDC42
    [Show full text]