Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency Disease

Total Page:16

File Type:pdf, Size:1020Kb

Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency Disease Bone Marrow Transplantation (2008) 41, 119–126 & 2008 Nature Publishing Group All rights reserved 0268-3369/08 $30.00 www.nature.com/bmt REVIEW Hematopoietic stem cell transplantation for primary immunodeficiency disease CC Dvorak and MJ Cowan Department of Pediatrics, Blood and Marrow Transplant Division, UCSF Children’s Hospital, San Francisco, CA, USA Hematopoietic stem cell transplantation is the definitive SCID therapy for a variety of rare primary cellular immuno- deficiency syndromes diagnosed in children. All primary SCID is a rare disease caused by a group of genetic immunodeficiencies benefit from early diagnosis and disorders with a shared phenotype of deficient T- and transplantation before the development of serious infec- B-lymphocyte function (with or without abnormal natural tions, which contribute to a significant increased risk of killer (NK) cell development) that leads to early death from mortality following transplant. In the absence of a recurrent infections in affected children (Table 2). In matched sibling, parental haplocompatible, matched un- addition, since SCID patients are unable to reject foreign related donor and cord blood stem cells have all been cells, a significant percentage of patients will have evidence utilized with varying degrees of success and immune of maternally engrafted T lymphocytes, which often leads reconstitution. The role of pretransplant conditioning in to clinical manifestations of GVHD.1 Exceptfor those patients with SCID disease in terms of its effects upon patients with SCID due to deficiency of adenosine T- and B-cell immune reconstitution and late effects is deaminase (ADA), for which a replacementenzyme exists, still under debate and will require further study. the only curative therapy for SCID is allogeneic HSCT. Bone Marrow Transplantation (2008) 41, 119–126; However, early results with gene insertion into autologous doi:10.1038/sj.bmt.1705890; published online 29 October 2007 hematopoietic stem cells for children with X-linked SCID Keywords: primary immunodeficiency; SCID; transplant- and ADA deficiency2 suggest that eventually, this will ation; HSCT become a more common form of curative treatment for many primary immunodeficiency diseases. At the time of diagnosis, patients with SCID generally have already developed, or are at an extremely elevated risk of developing, a life-threatening infection. This necessitates Introduction rapid initiation of HSCT. For all stem cell sources, successful outcomes are more likely to be achieved when Primary cellular immunodeficiencies are a group of the patient is still very young, preferably less than 6 months inherited disorders characterized by severe impairment of age.3,4 Buckley et al.,5 demonstrated that infants of the innate or adaptive immune systems, which transplanted less than 3.5 months of age had a 95% overall generally leads to early death from infectious complica- survival (OS), compared to only 76% OS in older children. tions. These disorders can be further categorized by the cell This is likely due to the development of pulmonary lineage(s) primarily affected (Table 1). While improved infections prior to transplant, which have been associated supportive care has extended the life span of patients with significantly poorer outcomes.4,6 In addition, trans- affected by these diseases, definitive cure is generally only plants performed within the first month of life are achieved by allogeneic hematopoietic stem cell transplanta- associated with more rapid T-cell reconstitution, perhaps tion (HSCT), though recent advances in gene therapy hold due to superior thymic capacity.7 significant promise that this may soon be a viable alternative. Impact of SCID phenotype T-B þ NKÀ SCID The mostcommon form of SCID, accountingfor approximately 50% of all cases, is due to a defect in the Correspondence: Dr MJ Cowan, Department of Pediatrics, Blood and gene for the common gamma chain (gc) located on Xq13. Marrow TransplantDivision, UCSF Children’s Hospital,505 Parnassus Another defect, JAK3 deficiency, results in a similar Avenue, San Francisco, CA 94143-1278, USA. E-mail: [email protected] T-B þ NKÀ phenotype (Table 2). Post transplant, patients Received 24 August 2007; revised 14 September 2007; accepted 14 with gc deficiency have been noted to have excellent rates of September 2007; published online 29 October 2007 sustained thymic output, as measured by levels of T-cell BMT for immunodeficiency diseases CC Dvorak and MJ Cowan 120 Table 1 Primary immunodeficiencies potentially treated with HSCT Absent T- and B- Defective T and B lymphocytes Dysfunctional T lymphocytes with Absent or dysfunctional granulocytes lymphocyte function predisposition to HLH SCID Wiskott–Aldrich syndrome Familial HLH (defects in perforin, Severe congenital neutropenia MUNC, etc.) HIGM1 Chediak–Higashi syndrome Leukocyte adhesion disorder Griscelli syndrome Chronic granulomatous disease XLP Abbreviations: HIGM1 ¼ hyper IgM syndrome (CD40 ligand deficiency); HLH ¼ hemophagocytic lymphohistiocytosis; XLP ¼ X-linked lymphoprolifera- tive disease. Table 2 Genetic subtypes of severe combined immunodeficiency Name Defect Phenotype Special X-linked Common g chain T-B+NKÀ JAK3 deficiency Janus kinase 3 T-B+NKÀ Rag 1 or 2 Recombinase-activating T-BÀNK+ Frequently associated with Omenn’s proteins 1 or 2 syndrome: autoreactive GVHD Artemis deficiency Artemis (also known as T-BÀNK+ Athabascan-speaking Native Americans, DCLRE1C) radiosensitive Ligase 4 deficiency Ligase 4 T-BÀNK+ Radiosensitive IL-7Ra deficiency IL-7 receptora T-B+NK+ CD45 deficiency CD45 T-B+NK+ CD3d deficiency CD3d subunitT-B+NK+ CD3e deficiency CD3e subunitT-B+NK+ CD3B deficiency CD3B subunitT-B+NK+ Cartilage hair hypoplasia Endoribonuclease T-B+NK+ Dwarfism, hypoplastic hair Finnish, Amish p56lck deficiency p56lck Protein tyrosine kinase T-B+NK+ ADA deficiency Adenosine deaminase T-BÀNKÀ PNP deficiency Purine nucleoside T-BÀNKÀ Neurologic dysfunction, ataxia phosphorylase Reticular dysgenesis Unknown T-BÀNKÀ Impaired myeloid and erythroid development, sensorineural deafness ZAP70 deficiency B-chain-associated protein kinase CD4+, CD8À B+, NK+ Bare lymphocyte Syndrome type II HLA class II CD4À(mild), CD8+ North African B+, NK+ SCID with bowel atresia Unknown CD4+, CD8+, B+NK+ Abbreviations: ADA ¼ adenosine deaminase; DCLREIC ¼ DNA cross-link repair enzyme 1C; HLA ¼ human leukocyte antigen. receptor excision circles (TRECs). This may be due to a has been attributed to a diminished rate of engraftment, pre-transplant low level of thymic precursors in these increased severity of GVHD, higher incidence of chronic patients, which post transplant allows for thymic seeding of GVHD4 and slower recovery of T-cell function.6,9 The very early progenitors.8 relatively poor engraftment in patients with T-BÀNK þ SCID is in large part due to the presence of host NK cells, which are capable of mediating donor stem cell rejection.4 T-BÀNK þ SCID Studies in animal models of NK þ SCID,10 as well as It has been estimated that 20–30% of all SCID cases have unpublished data in our own laboratory with an Artemis- the T-BÀNK þ phenotype with defects in RAG1 or RAG2 deficientmouse model, supporttherole of NK cells in graft being the most common etiology. It has been reported that resistance. B-phenotypes (presumably NK þ ) of SCID have signifi- cantly poorer 3-year OS (36%) compared with B þ phenotypes (64%).6 Bertrand et al.4 demonstrated a worse SCID due to DNA repair defects disease-free survival after T-depleted haplocompatible A subsetof T-B ÀNK þ SCID patients have increased transplant in patients with BÀ SCID (35%) compared cellular sensitivity to alkylating agents and ionizing with B þ SCID (60%). Haddad et al.9 has also shown a radiation, mainly due to a deficiency in the gene for worse long-term outcome in children with BÀ SCID (NK Artemis, a critical protein in the nonhomologous DNA cell phenotype unknown), who were more likely to die repair pathway.11 Unlike other forms of BÀ SCID, patients during the first 6 months post transplant (37%) compared with Artemis deficiency have undergone HSCT with with those who had B þ SCID (13%). This poor survival an excellentOS of 75%. 11 A new type of radiosensitive Bone Marrow Transplantation BMT for immunodeficiency diseases CC Dvorak and MJ Cowan 121 T-BÀNK þ SCID has been recently described with a defect cells from this source makes this option unfeasible for most in DNA ligase IV, an enzyme in the nonhomologous DNA cases of SCID, in which HSCT is urgently indicated. repair pathway distal to Artemis.12 Haplocompatible-related donors T-B þ NK þ SCID With the advent of effective T-cell depletion strategies, the Another subset of SCID patients is characterized by the use of haplocompatible family members as donors for presence of both B cells and NK cells. A variety of cellular children with SCID has become a viable strategy. Three- defects have been reported to result in this phenotype, year survivals of 53–79% have been reported, with including deficiencies of IL-7 receptor-a, CD45 and the significantly better success rates in more recent years and CD3d, CD3e and CD3B subunits. Most of these deficiencies in more experienced centers,3,5,6,14 especially if the trans- have only recently been discovered and very small numbers plantis performed early before thedevelopmentof life- of these patients have been followed long term after HSCT, threatening infections. In SCID patients with evidence of making definitive statements regarding their clinical course maternal engraftment,1 the mother is typically utilized as difficult. the stem cell source (unless an HLA-matched sibling is available), since the recipient is already tolerant to the maternal cells. A potential risk with this approach is the T þ SCID Rare forms of SCID are characterized by the selective development of GVHD by the maternally engrafted T cells following the infusion of maternal bone marrow cells. In absence of CD4 þ T cells (for example, HLA class II our own experience this has not been a significant problem deficiency) or CD8 þ T cells (for example, ZAP70 deficiency).
Recommended publications
  • IDF Patient & Family Handbook
    Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Diseases This book contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this book should not be used as a substitute for professional medical advice. FIFTH EDITION COPYRIGHT 1987, 1993, 2001, 2007, 2013 IMMUNE DEFICIENCY FOUNDATION Copyright 2013 by Immune Deficiency Foundation, USA. REPRINT 2015 Readers may redistribute this article to other individuals for non-commercial use, provided that the text, html codes, and this notice remain intact and unaltered in any way. The Immune Deficiency Foundation Patient & Family Handbook may not be resold, reprinted or redistributed for compensation of any kind without prior written permission from the Immune Deficiency Foundation. If you have any questions about permission, please contact: Immune Deficiency Foundation, 110 West Road, Suite 300, Towson, MD 21204, USA; or by telephone at 800-296-4433. Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficency Diseases 5th Edition This publication has been made possible through a generous grant from Baxalta Incorporated Immune Deficiency Foundation 110 West Road, Suite 300 Towson, MD 21204 800-296-4433 www.primaryimmune.org [email protected] EDITORS R. Michael Blaese, MD, Executive Editor Francisco A. Bonilla, MD, PhD Immune Deficiency Foundation Boston Children’s Hospital Towson, MD Boston, MA E. Richard Stiehm, MD M. Elizabeth Younger, CPNP, PhD University of California Los Angeles Johns Hopkins Los Angeles, CA Baltimore, MD CONTRIBUTORS Mark Ballow, MD Joseph Bellanti, MD R. Michael Blaese, MD William Blouin, MSN, ARNP, CPNP State University of New York Georgetown University Hospital Immune Deficiency Foundation Miami Children’s Hospital Buffalo, NY Washington, DC Towson, MD Miami, FL Francisco A.
    [Show full text]
  • Prof.Dr. TÜRKAN PATIROĞLU
    Prof.Dr. TÜRKAN PATIROĞLU Kişisel Bilgiler WE-epbo:s that:t pt:u/r/[email protected]/rturkanp/ ETığpitati Yman Bdail gUizlmeranilık, Erciyes Üniversitesi, Dahili Tıp Bil., Çocuk Sağlığı ve Hastalıkları, Türkiye 1998 - 2000 Tıpta UYazmndaanll ıUkz, mEracniylıeks, EÜrnciivyerss Üitnesivi,e Drsaihteilsi iT, Dıpa Bhiilli., TÇıopc Buikl. ,S Çaoğclıuğkı vSea ğHlaığsıt avleık Hlaarsıt, aTlüıkrlkairyı,e T 1ü9r7k7iy e- 11998828 - 1989 Yİnagbiliazcnec, Bı 2D Oilrltea rÜstü Sertifika, Kurs ve Eğitimler Sağlık ve Tıp, DEsesneenyt iHala Cylvinaniclaalr Rı Kesuellaarncıhm & S eGrCtiPfi kfoars ıT, Eriracli yInevse üsntiigvaetrosritse, sIni Hveasytvigaant oDre Anceaydleermi Yye, 2re0l1 E1tik Kurulu, 2008 Yaptığı Tezler STaıpğt.Va eU Hzmsta Andlık, 1, k9r8o2nik enfeksiyonu olan hastalarda glukoz metabolizması, Erciyes Üniversitesi, Tıp Fakültesi, Çocuk ASarğalışk tBırilimmlae rAi, lTaıpn, lDaarhıili Tıp Bilimleri, Çocuk Sağlığı ve Hastalıkları, Pediatrik Hematoloji, Pediatrik İmmünoloji ve Allerji APrkoaf.Ddre.,m Erickiy Uesn Üvnaivnelrasirte /si ,G Töıpr Feavklüeltresi, Çocuk Sağ.Ve Hst Ad, 1995 - Devam Ediyor YDrodç..DDorç., .DErrc.,i yEersc iÜyensiv Üenrsiviteerssii, tTeıspi, FTaıpk üFlateksüil, tÇeosic, uÇko cSuakğ .VSaeğ H.Vset AHdst, 1A9d9, 01 9- 8179 9- 51989 Yönetilen Tezler UPAzmTIaRnOlıĞk,L CU.E TR.,K HAENM(OÖFğrİLeİn Aci )H, A20ST0A6LARINDA F8 GENİ İNT22H BÖLGESİNDEKİ İNVERSİYONUN ARAŞTIRILMASI., Tıpta DPAÜTZIERYOLĞELRUİ VTE., DTİESDSAEMVİİ NETEK İNİNTLRİAĞVİ.,A TSıKptÜaL UEzRm KaOnAlıkG,Ü ML.AKSAYROANK ÜGKELCİÜŞ(TÖİRğrİLenEcNi) H, 2A0Y0V4ANLARDA ADRENOMEDÜLLİN KPARTAINRİOAĞLL RUA TD.,Y UOZTUENR ASPÜİRNEİLNİ EYTAKŞİALYEARNİ, TLıÖpStaE MUzİLmİ aHnAlıSkT, HA.LMAeRhDmAe tE(NÖDğrOeKnRciİ)N, 2F0O0N4KSİYONLARIN DEĞERLENDİRİLMESİ SCI. I, SGSeCneI tvice A AnHalCysIi sİn odf eak Csolehroirnt eo fG 2i7re5n P aDtieerngtisl ewridthe H Yyapyeırn-IlgaEn Saynn Mdraokmaelse laenrd/or Chronic MFruecdoe cNu.,t aRnoejaosu-Rse Cstarnepdoid Ji.,a Csaisballero Garcia de Oteyza A., Buchta M., Huebscher K., Gamez-Diaz L., Proietti M., JSOaUghRaNfAi SL.
    [Show full text]
  • 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
    [Show full text]
  • Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
    Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck.
    [Show full text]
  • Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168
    CASE REPORT published: 26 May 2017 doi: 10.3389/fimmu.2017.00576 Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168 Ivan K. Chinn1,2,3*†, Robert P. Sanders4†, Asbjørg Stray-Pedersen5,6,7, Zeynep H. Coban-Akdemir7,8, Vy Hong-Diep Kim9, Harjit Dadi9,10, Chaim M. Roifman9,10, Troy Quigg4, James R. Lupski1,7,8,11, Jordan S. Orange1,2,3 and I. Celine Hanson1,2 1 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA, 2 Section of Immunology, Allergy, and Rheumatology, Texas Children’s Hospital, Houston, TX, USA, 3 Center for Human Immunobiology, Texas Children’s Edited by: Hospital, Houston, TX, USA, 4 Texas Transplant Institute, Methodist Hospital, San Antonio, TX, USA, 5 Norwegian National Andrew Gennery, Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway, Newcastle University, UK 6 Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 7 Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, USA, 8 Department of Molecular and Human Genetics, Baylor College of Medicine, Reviewed by: Houston, TX, USA, 9 Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children, University Filomeen Haerynck, of Toronto, Toronto, ON, Canada, 10 Canadian Centre for Primary Immunodeficiency, The Jeffrey Model Research Laboratory Ghent University, Belgium for the Diagnosis of Primary Immunodeficiency, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, Kohsuke Imai, 11 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA Tokyo Medical and Dental University, Japan *Correspondence: With the advent of high-throughput genomic sequencing techniques, novel genetic Ivan K.
    [Show full text]
  • Host Genetics and Infectious Disease: New Tools, Insights and Translational Opportunities
    REVIEWS Host genetics and infectious disease: new tools, insights and translational opportunities Andrew J. Kwok 1, Alex Mentzer 1,2 and Julian C. Knight 1 ✉ Abstract | Understanding how human genetics influence infectious disease susceptibility offers the opportunity for new insights into pathogenesis, potential drug targets, risk stratification, response to therapy and vaccination. As new infectious diseases continue to emerge, together with growing levels of antimicrobial resistance and an increasing awareness of substantial differences between populations in genetic associations, the need for such work is expanding. In this Review, we illustrate how our understanding of the host–pathogen relationship is advancing through holistic approaches, describing current strategies to investigate the role of host genetic variation in established and emerging infections, including COVID-19, the need for wider application to diverse global populations mirroring the burden of disease, the impact of pathogen and vector genetic diversity and a broad array of immune and inflammation phenotypes that can be mapped as traits in health and disease. Insights from study of inborn errors of immunity and multi-omics profiling together with developments in analytical methods are further advancing our knowledge of this important area. Penetrance Disease syndromes caused by infectious agents have A seminal study of adoptees in the 1980s reported 1 The proportion of individuals occurred throughout the history of modern humans . increased risk of death from infectious disease in chil- with a particular genotype As a result of our continued interactions with patho- dren whose biological parents succumbed to an infec- that also has an associated gens, our genomes have been shaped through processes tious disease7, highlighting the significance of human phenotype.
    [Show full text]
  • Immune Cellular Evaluation Following Newborn Screening for Severe T
    In this issue: Clinical flow cytometry in 2019 This is a Platinum Open Access Journal distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Immune cellular evaluation following newborn screening for severe T and B cell lymphopenia Johannes Wolf1,2, Karolin Dahlenburg3, Stephan Borte2,4 1 Municipal Hospital St. Georg Leipzig, Academic Teaching Hospital of the University Leipzig, Department of Laboratory Medicine and Microbiology, Leipzig, Germany 2 Immuno Deficiency Center Leipzig (IDCL) at Hospital St. Georg Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiency Diseases, Leipzig, Germany 3 Faculty of Medicine, University Leipzig, Germany 4 Municipal Hospital St. Georg Leipzig, Academic Teaching Hospital of the University Leipzig, Department of Pediatrics, Leipzig, Germany ARTICLE INFO ABSTRACT Corresponding author: Newborn screening (NBS) for severe T and/or B cell Stephan Borte, MD, PhD Immuno Deficiency Center Leipzig (IDCL) lymphopenia to identify neonates with severe com- Hospital St. Georg Leipzig bined immunodeficiencies (SCID) or agammaglob- Delitzscher Strasse 141 ulinemia rapidly after birth has paved its way into D-04129 Leipzig clinical practice. Debate exists on the concept and Germany Phone: +49 341 909 4478 strategy for rapid verification and stratification of the E-mail: [email protected] cellular immune status of positively screened infants. We provide impulses for harmonization of flow cyto- Key words: newborn screening, T cell lymphopenia, metric approaches to allow rapid integration in the B cell lymphopenia, severe combined growing number of immunological laboratories in- immunodeficiency volved in follow-up and subdivision of SCID and non- Acknowledgement: SCID entities.
    [Show full text]
  • Blueprint Genetics Severe Combined Immunodeficiency Panel
    Severe Combined Immunodeficiency Panel Test code: IM0101 Is a 80 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of combined immunodeficiencies. The genes on this panel are included in the Primary Immunodeficiency Panel. About Severe Combined Immunodeficiency Severe combined immunedeficiencies (SCIDs) are a group of primary immunodeficiencies characterized by specific mutations in genes of T and B-lymphocyte systems and leading to little or no immune response. Different subtypes of SCIDs are characterized and subdivided by the presence of circulating T and B cells. T cells are absent or markedly decreased in the most types, but levels of B cells vary. In addition, both of these disease subgroups (T-B+ and T-B-) can occur with or without NK cells. Patients with SCID are susceptible to recurrent infections that can be fatal. The worldwide prevalence of SCID is estimated to be at least 1:100,000 births, while some genetically more homogenous populations may show markedly increased numbers. Mutations in IL2RG are the most common reason for SCIDs, explaining approximately 50% of all cases and close to 100% of X-linked cases. Availability 4 weeks Gene Set Description Genes in the Severe Combined Immunodeficiency Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ADA Severe combined immunodeficiency due to adenosine deaminase AR 49 93 deficiency AK2 Reticular dysgenesis AR 14 17 ATM Breast cancer, Ataxia-Telangiectasia AD/AR 1047 1109 BCL11B Immunodeficiency
    [Show full text]
  • Primary Immunodeficiency Diseases in Children and Adults
    Primary Immunodeficiency Diseases in children and adults Microorganism Primary Immune Deficiency Diseases Disease (PID) Environment Host • Background • Approach to diagnosis of PID • Genetic diagnosis of PID • Lack of focus is good thing • Looks like duck but not a duck Primary Immunodeficiency diseases • Inherited diseases of immune system • Affect different components of the immune system • Clinically heterogeneous Why do we need to diagnose PIDs? • Collective Prevalence of high as 1 in 10000 suggesting a very high burden of disease • Often missed causing significant morbidity and mortality • Multiple family members may get affected leading to financial burden on the family and society • Early diagnosis and adequate management can lead to significant reduction in morbidity and mortality Group Category Group I Combined immunodeficiencies Group II Combined immunodeficiencies with associated or syndromic features. Group III Predominantly antibody deficiencies. Group IV Diseases of immune dysregulation. Group V Congenital defects of phagocyte number, function, or both. Group VI Defects in innate immunity. Group VII Autoinflammatory disorders. Group VIII Complement deficiencies. Group IX Phenocopies of PID • International Union of Immunological Societies (IUIS): • 354 distinct disorders • 344 different gene defects listed (Feb2017) Group I Combined immunodeficiencies Group IV Diseases of immune Group II Combined immunodeficiencies with dysregulation. associated or syndromic features. Group VII Autoinflammatory Group III Predominantly antibody disorders.
    [Show full text]
  • Molecular Genetic Testing
    Request for Molecular Genetic Testing Diagnostic Laboratories Department of Pediatrics Informed consent of patient and Adolescent Medicine The German. law (Gendiagnostikgesetz – GenDG) defines under which Medical Director: Prof. Dr. K.-M. Debatin circumstances genetic testing of a human individual is legal. Diagnostic testing Prof. Dr. Georgia Lahr! can only be conducted with the patient’s informed consent which requires documented consultation with a doctor. Predictive testing requires genetic Molecular Diagnostics Laboratory! counselling by a human genetics specialist prior to and after the investigation, University Medical Center Ulm! or the patient’s written renunciation. Eythstrasse 24 - D-89075 Ulm Please fill out the informed consent carefully and completely and sign it. Germany Otherwise no molecular genetic testing can be performed! Molecular Genetic Testing 3-5 ml EDTA-blood (send by normal mail) Turnaround time: 2-4 weeks, more than one analysis and rare analyses may take up to 8 weeks OMIM Disease Gene Immunology Immunodeficiency SCID (T-B+) q OMIM 300400 Severe Combinined Immunodeficiency (SCID, X-chromosomal, T-, B+, NK- ) IL2RG q OMIM 606367 Severe Combinined Immunodeficiency, CD25 deficiency IL2RA q OMIM 600802 Severe Combinined Immunodeficiency (SCID, T-, B+, NK- ), JAK3 deficiency JAK3 q OMIM 608971 Severe Combinined Immunodeficiency (SCID, T- B+ NK+ ), IL7R deficiency IL7R q OMIM 608971 Severe Combinined Immunodeficiency (SCID, T- B+ NK+ ), CD3D deficiency CD3D q OMIM 608971 Severe Combinined Immunodeficiency (SCID, T-
    [Show full text]
  • Pulmonary Complications of Primary Immunodeficiencies
    PAEDIATRIC RESPIRATORY REVIEWS (2004) 5(Suppl A), S225–S233 Pulmonary complications of primary immunodeficiencies Rebecca H. Buckley° Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710, USA Summary In the fifty years since Ogden Bruton discovered agammaglobulinemia, more than 100 additional immunodeficiency syndromes have been described. These disorders may involve one or more components of the immune system, including T, B, and NK lymphocytes; phagocytic cells; and complement proteins. Most are recessive traits, some of which are caused by mutations in genes on the X chromosome, others in genes on autosomal chromosomes. Until the past decade, there was little insight into the fundamental problems underlying a majority of these conditions. Many of the primary immunodeficiency diseases have now been mapped to specific chromosomal locations, and the fundamental biologic errors have been identified in more than 3 dozen. Within the past decade the molecular bases of 7 X-linked immunodeficiency disorders have been reported: X-linked immunodeficiency with Hyper IgM, X-linked lymphoproliferative disease, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency, the Wiskott–Aldrich syndrome, nuclear factor úB essential modulator (NEMO or IKKg), and the immune dysregulation polyendocrinopathy (IPEX) syndrome. The abnormal genes in X-linked chronic granulomatous disease (CGD) and properdin deficiency had been identified several years earlier. In addition, there are now many autosomal recessive immunodeficiencies for which the molecular bases have been discovered. These new advances will be reviewed, with particular emphasis on the pulmonary complications of some of these diseases. In some cases there are unique features of lung abnormalities in specific defects.
    [Show full text]
  • Investigations on the Molecular Biology of Human Adenylate
    Ulm University Medical Center Institute for Transfusion Medicine Prof. Dr. med. Hubert Schrezenmeier Investigations on the Molecular Biology of Human Adenylate Kinase 2 Deficiency (Reticular Dysgenesis) and the Establishment and Characterisation of an Adenylate Kinase 2-deficient Mouse Model Dissertation to obtain the doctoral degree of Human Biology (Dr. biol. hum.) of the Medical Faculty of Ulm University Rebekka Waldmann Ulm 2017 Amtierender Dekan: Prof. Dr. rer. nat. Thomas Wirth 1. Berichterstatter: Prof. Dr. med. Hubert Schrezenmeier 2. Berichterstatter: PD Dr. med. Manfred Hönig Tag der Promotion: 13.04.2018 Index Index INDEX OF ABBREVIATIONS ........................................................................................................................... I 1 INTRODUCTION ..................................................................................................................................... 1 1.1 SEVERE COMBINED IMMUNODEFICIENCIES (SCIDS) ........................................................................................ 1 1.2 RETICULAR DYSGENESIS ............................................................................................................................. 2 1.3 ADENYLATE KINASES ................................................................................................................................. 3 1.4 IMMUNODEFICIENT MOUSE MODELS ........................................................................................................... 7 1.5 AIM OF THE STUDY ..................................................................................................................................
    [Show full text]