DOCSLIB.ORG

Growth Patterns of Patients with Noonan Syndrome: Correlation with Age and Genotype

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

174:5 C Cessans, V Ehlinger and Growth patterns of Noonan 174:5 641–650 Clinical Study others syndrome Growth patterns of patients with Noonan syndrome: correlation with age and genotype Catie Cessans1,*, Virginie Ehlinger2,*, Catherine Arnaud2,3, Armelle Yart4, Yline Capri5, Pascal Barat6, Benoit Cammas6, Didier Lacombe7, Régis Coutant8, Albert David9, Sabine Baron10, Jacques Weill11, Bruno Leheup12, Marc Nicolino13, Jean-Pierre Salles1,14, Alain Verloes5, Maithé Tauber1,14, Hélène Cavé5 and Thomas Edouard1,14 1Endocrine, Bone Diseases, and Genetics Unit, Children’s Hospital, Toulouse University Hospital, Toulouse, France, 2UMR 1027 INSERM, University of Toulouse Paul Sabatier, Toulouse, France, 3Clinical Epidemiology Unit, Toulouse University Hospital, Toulouse, France, 4INSERM UMR 1048, Institute of Cardiovascular and Metabolic Diseases (I2MC), University of Toulouse Paul Sabatier, Toulouse, France, 5Departments of Genetics, Robert-Debré University Hospital, APHP, Paris, France, 6Pediatric Endocrinology Department, Clinical investigation Centre (CIC 1401), Bordeaux University Hospital, Bordeaux, France, 7Genetics Department, Bordeaux University Hospital, EA4576, Bordeaux, France, 8Pediatric Endocrinology Department, Angers University Hospital, Angers, France, 9 10 Genetics Department, Nantes University Hospital, Nantes, France, Pediatric Endocrine Unit, Nantes University Correspondence 11 12 Hospital, Nantes, France, Pediatric Endocrine Unit, Lille University Hospital, Lille, France, Pediatric and should be addressed 13 Genetics Unit, Nancy University Hospital, Vandoeuvre, France, Pediatric Endocrinology Department, to T Edouard 14 Lyon University Pediatric Hospital, INSERM U.1060/UCBL/HCL, France, INSERM UMR 1043, Centre of Email Pathophysiology of Toulouse Purpan (CPTP), University of Toulouse Paul Sabatier, Toulouse, France [email protected] *(C Cessans and V Ehlinger contributed equally to this work.) Abstract Background: Growth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified. Objective: The goal of this study was to compare growth parameters according to genotype in patients with NS. Subjects and methods: The study population included 420 patients (176 females and 244 males) harboring mutations in European Journal European of Endocrinology the PTPN11, SOS1, RAF1, or KRAS genes. NS-associated PTPN11 mutations (NS-PTPN11) and NS with multiple lentigines- associated PTPN11 mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes. Results: Patients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4; P < 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P < 0.001). At birth, patients with NS-PTPN11 were significantly shorter and thinner than patients with NSML-PTPN11, SOS1, or KRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients with NSML-PTPN11 and SOS1 than in patients with NS-PTPN11 (P < 0.001 and P = 0.002 respectively). Patients with NS had lower BMI at 10 years (P < 0.001). No difference between genotypes was demonstrated. Conclusion: Determining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients. European Journal of Endocrinology (2016) 174, 641–650 Introduction Noonan syndrome (NS; Mendelian inheritance in man features, heart defects (i.e. pulmonary valve stenosis and (MIM) #163950) is a relatively frequent (estimated hypertrophic cardiomyopathy), developmental delay, prevalence of 1 in 1000 – 2500 live births) autosomal and short stature (1). These distinctive traits are shared, dominant disorder characterized by facial dysmorphic with variable severity, by NS-related diseases, namely NS www.eje-online.org © 2016 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0922 PrintedinGreat Britain Downloaded from Bioscientifica.com at 09/28/2021 04:48:29AM via free access 10.1530/EJE-15-0922 Clinical Study C Cessans, V Ehlinger and Growth patterns of Noonan 174:5 642 others syndrome with multiple lentigines (NSML; MIM #151100), NS with symptoms of NS that lead to the diagnosis (12). Specific loose anagen hair (MIM #607721), cardiofaciocutaneous growth charts were established more than 25 years ago syndrome (MIM #115150), Costello syndrome (MIM (13, 14) before the genes involved in NS were identi- 218040), and neurofibromatosis type I (MIM #162200). fied. The discovery of these genes made it possible to In the past decade, mutations in several genes encoding look for genotype–phenotype correlations in growth components of the RAS/MAPK signaling pathway patterns. However, to our knowledge, only one study were discovered to be involved in NS and NS-related investigated the growth characteristics according to diseases, and this group of disorders is now termed the genotype in 127 patients with NS and 10 patients with RASopathies (2). They are one of the largest groups of NS-related diseases, with interesting preliminary results multiple congenital anomaly diseases known. (15). In this study, growth parameters (height, weight, The classical form of NS is principally associated and body mass index (BMI)) were converted to age-spe- with heterozygous missense mutations in four genes: cific and sex-specific standard deviations on the basis of PTPN11, SOS1, RAF1, and KRAS genes, accounting for children’s growth standards, and then cumulated before 50, 10, 10, and <2%, respectively, of the NS cases (1). searching for differences between genotypes. As a result, A dozen genes have been found to be implicated in NS, variations according to age and genotype could not be but genetic screening remains negative in about 30% of investigated. patients with NS. In this study, we aimed to describe the growth char- NSML, previously referred as LEOPARD syndrome acteristics (i.e. measurements at birth, height, and BMI) (acronym for multiple Lentigines, Electrocardiographic of patients with NS and NSML according to their age and conduction abnormalities, Ocular hypertelorism, Pulmo- genotype, and evaluate whether mutations in the differ- nary stenosis, Abnormal genitalia, Retardation of growth, ent genes involved in NS and NSML may have differential sensorineural Deafness), is closely related to NS. Indeed, impact in growth. To achieve this goal, we took advan- because lentigines appear with age, these two syndromes tage of a French national database and present the growth might be difficult to differentiate in early life. NSML is parameters at different ages according to their genotype allelic with NS, being mainly caused by PTPN11 (12q24.13) in 420 patients with NS or NSML harboring mutations in mutations (>80% of patients) and more rarely by RAF1 the PTPN11, SOS1, RAF1, or KRAS genes. (3p25.2) mutations (3, 4). So far, more than 60 mutations in PTPN11 have been associated with NS, which mainly affect the interaction between the SH2 and the protein Subjects and methods European Journal European of Endocrinology tyrosine phosphatase (PTP) domains, and about 20 muta- Patient population tions, all targeting specific residues within the PTP domain, have been linked to NSML (5). The PTPN11 gene encodes The majority of French patients with NS and NS-related Shp2, a widely expressed nonreceptor PTP that plays key disorders are referred for molecular testing to the roles in organism development and homeostasis by con- Department of Genetics of Robert-Debré Hospital (Paris, trolling major growth factors/hormone-triggered signal- France). The clinical data are recorded by the clinicians ing pathways, notably the RAS/MAPK pathway (6). From on standard datasheets. The data include, among other a biochemical point of view, it has been shown that NS- features, the gestational age and measurements at birth causing mutations induce hyperactivation of the phospha- (weight, length, and head circumference), and the height tase (gain-of-function mutation), while NSML-associated and weight at the time of consultation, at 2, 5, 10 years of mutations result in reduced Shp2 catalytic activity (inac- age, and in adulthood. Treatment with growth hormone tivating mutation) (7, 8). How NS-Shp2 and NSML-Shp2 (GH) is also recorded. mutants can result in related syndromes while displaying The study was approved by the Paris-Bichat-Claude opposite biochemical effects is still a matter of debate (9). Bernard Institutional Review Board (n°2003/15) and Interestingly, a differential impact of these mutants on the informed consent was obtained from legal guardians for phosphatidylinositol 3-kinase (PI3K)/Akt signaling path- genetic analyses and for building up the database. way has been causally linked to the development of hyper- Inclusion criteria for our study were a diagnosis of trophic cardiomyopathy, which is preferentially found in NS or NSML between 2002 and 2012, caused by germline patients with NSML (10, 11). mutations in one of the following genes: PTPN11, Proportionate short stature, reported in more than SOS1, RAF1, or KRAS. Two types of PTPN11 mutations 70% of affected patients, is one of the main clinical were distinguished: NS-associated PTPN11 mutations www.eje-online.org Downloaded
Recommended publications
  • Intersectin 1 Forms Complexes with SGIP1 and Reps1 in Clathrin-Coated

    Intersectin 1 Forms Complexes with SGIP1 and Reps1 in Clathrin-Coated

    Biochemical and Biophysical Research Communications 402 (2010) 408–413 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Intersectin 1 forms complexes with SGIP1 and Reps1 in clathrin-coated pits ⇑ Oleksandr Dergai a, ,1, Olga Novokhatska a,1, Mykola Dergai a, Inessa Skrypkina a, Liudmyla Tsyba a, Jacques Moreau b, Alla Rynditch a a Department of Functional Genomics, Institute of Molecular Biology and Genetics, NASU, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine b Molecular Mechanisms of Development, Jacques Monod Institute, Development and Neurobiology Program, UMR7592 CNRS – Paris Diderot University, 15 rue Hélène Brion, 75205 Paris Cedex 13, France article info abstract Article history: Intersectin 1 (ITSN1) is an evolutionarily conserved adaptor protein involved in clathrin-mediated endo- Received 7 October 2010 cytosis, cellular signaling and cytoskeleton rearrangement. ITSN1 gene is located on human chromosome Available online 12 October 2010 21 in Down syndrome critical region. Several studies confirmed role of ITSN1 in Down syndrome pheno- type. Here we report the identification of novel interconnections in the interaction network of this endo- Keywords: cytic adaptor. We show that the membrane-deforming protein SGIP1 (Src homology 3-domain growth Endocytosis factor receptor-bound 2-like (endophilin) interacting protein 1) and the signaling adaptor Reps1 (RalBP Adaptor proteins associated Eps15-homology domain protein) interact with ITSN1 in vivo. Both interactions are mediated Intersectin 1 by the SH3 domains of ITSN1 and proline-rich motifs of protein partners. Moreover complexes compris- Protein interactions SGIP1 ing SGIP1, Reps1 and ITSN1 have been identified. We also identified new interactions between SGIP1, Reps1 Reps1 and the BAR (Bin/amphiphysin/Rvs) domain-containing protein amphiphysin 1.
  • To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants

    To Study Mutant P53 Gain of Function, Various Tumor-Derived P53 Mutants

    Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By Shama K Khokhar M.Sc., Bilaspur University, 2004 B.Sc., Bhopal University, 2002 2007 1 COPYRIGHT SHAMA K KHOKHAR 2007 2 WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES Date of Defense: 12-03-07 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY SHAMA KHAN KHOKHAR ENTITLED Differential effects of mutant TAp63γ on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science Madhavi P. Kadakia, Ph.D. Thesis Director Daniel Organisciak , Ph.D. Department Chair Committee on Final Examination Madhavi P. Kadakia, Ph.D. Steven J. Berberich, Ph.D. Michael Leffak, Ph.D. Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies 3 Abstract Khokhar, Shama K. M.S., Department of Biochemistry and Molecular Biology, Wright State University, 2007 Differential effect of TAp63γ mutants on transactivation of p53 and/or p63 responsive genes and their effects on global gene expression. p63, a member of the p53 gene family, known to play a role in development, has more recently also been implicated in cancer progression. Mice lacking p63 exhibit severe developmental defects such as limb truncations, abnormal skin, and absence of hair follicles, teeth, and mammary glands. Germline missense mutations of p63 have been shown to be responsible for several human developmental syndromes including SHFM, EEC and ADULT syndromes and are associated with anomalies in the development of organs of epithelial origin.
  • Advances in Understanding the Genetics of Syndromes Involving Congenital Upper Limb Anomalies

    Advances in Understanding the Genetics of Syndromes Involving Congenital Upper Limb Anomalies

    Review Article Page 1 of 10 Advances in understanding the genetics of syndromes involving congenital upper limb anomalies Liying Sun1#, Yingzhao Huang2,3,4#, Sen Zhao2,3,4, Wenyao Zhong1, Mao Lin2,3,4, Yang Guo1, Yuehan Yin1, Nan Wu2,3,4, Zhihong Wu2,3,5, Wen Tian1 1Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China; 2Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; 3Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing 100730, China; 4Department of Orthopedic Surgery, 5Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China Contributions: (I) Conception and design: W Tian, N Wu, Z Wu, S Zhong; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Y Huang; (V) Data analysis and interpretation: L Sun; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Wen Tian. Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China. Email: [email protected]. Abstract: Congenital upper limb anomalies (CULA) are a common birth defect and a significant portion of complicated syndromic anomalies have upper limb involvement. Mostly the mortality of babies with CULA can be attributed to associated anomalies. The cause of the majority of syndromic CULA was unknown until recently. Advances in genetic and genomic technologies have unraveled the genetic basis of many syndromes- associated CULA, while at the same time highlighting the extreme heterogeneity in CULA genetics. Discoveries regarding biological pathways and syndromic CULA provide insights into the limb development and bring a better understanding of the pathogenesis of CULA.
  • Level Estimates of Maternal Smoking and Nicotine Replacement Therapy During Pregnancy

    Level Estimates of Maternal Smoking and Nicotine Replacement Therapy During Pregnancy

    Using primary care data to assess population- level estimates of maternal smoking and nicotine replacement therapy during pregnancy Nafeesa Nooruddin Dhalwani BSc MSc Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy November 2014 ABSTRACT Background: Smoking in pregnancy is the most significant preventable cause of poor health outcomes for women and their babies and, therefore, is a major public health concern. In the UK there is a wide range of interventions and support for pregnant women who want to quit. One of these is nicotine replacement therapy (NRT) which has been widely available for retail purchase and prescribing to pregnant women since 2005. However, measures of NRT prescribing in pregnant women are scarce. These measures are vital to assess its usefulness in smoking cessation during pregnancy at a population level. Furthermore, evidence of NRT safety in pregnancy for the mother and child’s health so far is nebulous, with existing studies being small or using retrospectively reported exposures. Aims and Objectives: The main aim of this work was to assess population- level estimates of maternal smoking and NRT prescribing in pregnancy and the safety of NRT for both the mother and the child in the UK. Currently, the only population-level data on UK maternal smoking are from repeated cross-sectional surveys or routinely collected maternity data during pregnancy or at delivery. These obtain information at one point in time, and there are no population-level data on NRT use available. As a novel approach, therefore, this thesis used the routinely collected primary care data that are currently available for approximately 6% of the UK population and provide longitudinal/prospectively recorded information throughout pregnancy.
  • Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)

    Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)

    824 ONCOLOGY REPORTS 45: 824-834, 2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review) KAILI LUO1, LEI ZHANG2, YUAN LIAO1, HONGYU ZHOU1, HONGYING YANG2, MIN LUO1 and CHEN QING1 1School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500; 2Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China Received August 29, 2020; Accepted December 9, 2020 DOI: 10.3892/or.2021.7927 Abstract. Epidermal growth factor receptor pathway substrate 8 1. Introduction (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which Malignant tumours are uncontrolled cell proliferation diseases is involved in cell mitosis, differentiation and other physiological caused by oncogenes and ultimately lead to organ and body functions. Numerous studies over the last decade have demon- dysfunction (1). In recent decades, great progress has been strated that Eps8 is overexpressed in most ubiquitous malignant made in the study of genes and signalling pathways in tumours and subsequently binds with its receptor to activate tumorigenesis. Eps8 was identified by Fazioli et al in NIH-3T3 multiple signalling pathways. Eps8 not only participates in the murine fibroblasts via an approach that allows direct cloning regulation of malignant phenotypes, such as tumour proliferation, of intracellular substrates for receptor tyrosine kinases (RTKs) invasion, metastasis and drug resistance, but is also related to that was designed to study the EGFR signalling pathway. Eps8 the clinicopathological characteristics and prognosis of patients.
  • Time Resolved Quantitative Phosphoproteomics Reveals Distinct Patterns of SHP2

    Time Resolved Quantitative Phosphoproteomics Reveals Distinct Patterns of SHP2

    bioRxiv preprint doi: https://doi.org/10.1101/598664; this version posted April 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Time resolved quantitative phosphoproteomics reveals distinct patterns of SHP2 dependence in EGFR signaling Vidyasiri Vemulapalli1,2, Lily Chylek3, Alison Erickson4, Jonathan LaRochelle1,2, Kartik Subramanian3, Morvarid Mohseni5, Matthew LaMarche5, Michael G. Acker5, Peter K. Sorger3, Steven P. Gygi4, and Stephen C. Blacklow1,2* 1Department of Cancer Biology, Dana-Farber Cancer Institute Boston, MA 02115, USA 2Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA 3Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA 4Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA 5Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA *To whom correspondence should be addressed: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/598664; this version posted April 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract SHP2 is a protein tyrosine phosphatase that normally potentiates intracellular signaling by growth factors, antigen receptors, and some cytokines; it is frequently mutated in childhood leukemias and other cancers. Here, we examine the role of SHP2 in the responses of breast cancer cells to EGF by monitoring phosphoproteome dynamics when SHP2 is allosterically inhibited by the small molecule SHP099.
  • The Regulatory Roles of Phosphatases in Cancer

    The Regulatory Roles of Phosphatases in Cancer

    Oncogene (2014) 33, 939–953 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW The regulatory roles of phosphatases in cancer J Stebbing1, LC Lit1, H Zhang, RS Darrington, O Melaiu, B Rudraraju and G Giamas The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies. Oncogene (2014) 33, 939–953; doi:10.1038/onc.2013.80; published online 18 March 2013 Keywords: cancer; phosphatases; solid tumours GASTROINTESTINAL MALIGNANCIES abs in sera were significantly associated with poor survival in Oesophageal cancer advanced ESCC, suggesting that they may have a clinical utility in Loss of PTEN (phosphatase and tensin homologue deleted on ESCC screening and diagnosis.5 chromosome 10) expression in oesophageal cancer is frequent, Cao et al.6 investigated the role of protein tyrosine phosphatase, among other gene alterations characterizing this disease. Zhou non-receptor type 12 (PTPN12) in ESCC and showed that PTPN12 et al.1 found that overexpression of PTEN suppresses growth and protein expression is higher in normal para-cancerous tissues than induces apoptosis in oesophageal cancer cell lines, through in 20 ESCC tissues.
  • PTPN11 Is the First Identified Proto-Oncogene That Encodes a Tyrosine Phosphatase

    PTPN11 Is the First Identified Proto-Oncogene That Encodes a Tyrosine Phosphatase

    From www.bloodjournal.org by guest on July 4, 2016. For personal use only. Review article PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase Rebecca J. Chan1 and Gen-Sheng Feng2,3 1Department of Pediatrics, the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; 2Programs in Signal Transduction and Stem Cells & Regeneration, Burnham Institute for Medical Research, La Jolla, CA; 3Institute for Biomedical Research, Xiamen University, Xiamen, China Elucidation of the molecular mechanisms 2 Src-homology 2 (SH2) domains (Shp2). vation of the Ras-Erk pathway. This underlying carcinogenesis has benefited This tyrosine phosphatase was previ- progress represents another milestone in tremendously from the identification and ously shown to play an essential role in the leukemia/cancer research field and characterization of oncogenes and tumor normal hematopoiesis. More recently, so- provides a fresh view on the molecular suppressor genes. One new advance in matic missense PTPN11 gain-of-function mechanisms underlying cell transforma- this field is the identification of PTPN11 mutations have been detected in leuke- tion. (Blood. 2007;109:862-867) as the first proto-oncogene that encodes mias and rarely in solid tumors, and have a cytoplasmic tyrosine phosphatase with been found to induce aberrant hyperacti- © 2007 by The American Society of Hematology Introduction Leukemia and other types of cancer continue to be a leading cause tumor suppressor activity when overexpressed in vitro, and Ptprj of death in the United States, and biomedical scientists sorely note maps to the mouse colon cancer susceptibility locus,3 implicating that victories against cancer remain unacceptably rare.
  • Orphanet Report Series Rare Diseases Collection

    Orphanet Report Series Rare Diseases Collection

    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
  • Noonan Syndrome and Related Disorders Sos1, Raf1, Kras & Shoc2 Gene Sequencing

    Noonan Syndrome and Related Disorders Sos1, Raf1, Kras & Shoc2 Gene Sequencing

    Molecular Diagnostic Laboratory 1600 Rockland Road, Wilmington, DE 19803 302.651.6775 email: [email protected] NOONAN SYNDROME AND RELATED DISORDERS SOS1, RAF1, KRAS & SHOC2 GENE SEQUENCING Noonan syndrome (OMIM 163950) is an autosomal dominant disorder due to mutations in several genes that are involved in the Ras-mitogen-activated protein kinase (RAS/MapK) pathway. Specifically, Noonan syndrome is caused by mutations in PTPN11* (OMIM 176876), SOS1 (OMIM 182530), RAF1 (OMIM 164760), and KRAS (OMIM 190070). Noonan syndrome is characterized by heart defects including hypertrophic cardiomyopathy and pulmonic valve stenosis, facial dysmorphology, short stature, chest wall deformities, and developmental delay. Noonan syndrome-like disorder with loose anagen hair (OMIM 607721) is a closely related disorder characterized by the above features as well as actively growing hair that is sparse, easy to pluck, thin, and slow-growing. This related disorder is due to mutations in SHOC2 (OMIM 602775), which is also involved in the RAS/MapK pathway. PTPN11* and RAF1 are also associated with LEOPARD syndrome (OMIM 151100). LEOPARD syndrome is an acronym for multiple lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. LEOPARD syndrome is an autosomal dominant disorder, and can present much like Noonan syndrome with additional features. * Please note: We are no longer able to offer diagnostic testing for the PTPN11 gene due to patent restrictions enforced by U.S. Patent 7,335,469. Testing: Testing can be performed in tiers, moving to the next tier only if the preceding test is negative. Testing can also be performed concurrently or in any order requested.
  • Intersectin-1S Deficiency in Pulmonary Pathogenesis Niranjan Jeganathan1*, Dan Predescu2 and Sanda Predescu3

    Intersectin-1S Deficiency in Pulmonary Pathogenesis Niranjan Jeganathan1*, Dan Predescu2 and Sanda Predescu3

    Jeganathan et al. Respiratory Research (2017) 18:168 DOI 10.1186/s12931-017-0652-4 REVIEW Open Access Intersectin-1s deficiency in pulmonary pathogenesis Niranjan Jeganathan1*, Dan Predescu2 and Sanda Predescu3 Abstract Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFβRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EHITSN and SH3A-EITSN fragments. The EHITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EHITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology.
  • 349 D.R. Laub Jr. (Ed.), Congenital Anomalies of the Upper

    349 D.R. Laub Jr. (Ed.), Congenital Anomalies of the Upper

    Index A dermatological anomalies , 182 Abductor digiti minimi (ADM) transfer , 102–103 skeletal abnormalities , 182 Abductor pollicis brevis (APB) , 186–187 upper extremity anomalies , 182, 183 ABS. See Amniotic band syndrome (ABS) visceral anomalies , 182 Achondroplasia defi nition of , 179 classifi cation/characterization , 338 description , 32, 33 defi nition of , 337–338 epidemiology of , 181 genetics , 338 genetics and embryology management , 338 molecular etiology , 180 Acrocephalosyndactyly syndrome , 32, 33, 179 prenatal diagnosis , 180–181 Acrosyndactyly repair, ABS , 300–302 molecular basis of , 180 Adactylic group IV symbrachydactyly , 129, 131 postoperative care and complications , 187 Al-Awadi syndrome , 154 treatment Amniotic band syndrome (ABS) APB release , 186–187 acrosyndactyly repair , 300–302 border digits syndactylies , 184 anesthesia concerns of fi rst web space release , 186 induction and maintenance of anesthesia , 43 patient age , 183 postoperative concerns , 43 secondary revisions , 187 preoperative preparation , 42–43 symphalangism , 184 classifi cation , 298 syndactyly ( see Syndactyly) clinical presentation thumb radial clinodactyly , 186–187 acrosyndactyly , 297–298 type II apert hand , 187–188 digital malformation , 297 Apical ectodermal ridge (AER) , 3–5 distal skeletal bones tapering , 297–298 Arthrogryposis , 210 hand deformity , 297 classic arthrogryposis , 305–306, 308 complications , 302 classifi cation , 305, 306 constriction band release defi nition of , 229, 230, 305 Upton’s technique , 299, 301 de-rotation osteotomy, shoulder , 308, 309 z-plasty , 299–300 distal , 230–231 ( see Distal arthrogryposis) diagnosis of , 296 elbow treatment digital hypoplasia reconstruction , 302 muscle transfers , 310–311 etiology of , 295–296 nonoperative management , 308 preoperative considerations , 299 posterior elbow capsular release , 309 treatment , 299 radial head dislocations , 311 Amniotic constriction band syndrome.