Table Of ContentStiehm’s Immune Deficiencies
Stiehm’s Immune Deficiencies
Edited by
Kathleen E. Sullivan
E. Richard Stiehm
Associate Editors
Luigi D. Notarangelo
Steven M. Holland
Charlotte Cunningham-Rundles
Alain Fischer
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Preface
This book follows in the steps of Immunologic Disorders his younger colleagues Max Cooper, Richard Hong,
in Infants and Children, first published in 1974, the fifth Paul Quie, et al.)and CharlesJanewayof Boston (and his
edition of which was published in 2005. Now entitled younger colleagues David Gitlin, Fred Rosen, Ralph
Stiehm’s Immune Deficiencies, this volume narrows its Wedgwood, et al.). These individuals spurred the devel-
focus from all aspects of pediatric immunology to that opment of many of the immunodeficiency study centers
of immunodeficiencies in children and adults. Yet the throughout North America and served as mentors for
size of the book remains approximately the same as mostoftheAmericanimmunodeficiencyspecialists.
Immunologic Disorders in Infants and Children, reflect- Forty years have passed and a great immunologic
ing the enormous advances in the study of immunodefi- awakening has come forth throughout the globe. Thus, a
ciency, including the description of new syndromes, suitable subtitle of this edition might be “A Tale of Five
investigating their pathogenesis, and delineating new Continents,” as half of the contributors are from Europe,
treatments. SouthAmerica,Asia,andAustralia.
Thefirstimmunodeficiencysyndromeswereidentified This book details the most notable trends in the field,
by European physicians, including congenital neutropenia including newly described syndromes, genetic diagnosis,
in 1922 by W. Schultz in Berlin, ataxia-telangiectasia in molecular abnormalities, newborn screening, and current
1926 (by L. Syllaba and K. Henner in Paris), Wiskott- therapies, including immunoglobulin use, stem cell trans-
Aldrich syndrome by in 1937 (by A. Wiskott in Munich), plants, cytokine and monoclonal antibody therapy, gene
and lymphopenic agammaglobulinemia in 1950 by therapy, disease registries, and regional registries.
E.GlanzmannandP.RinikerinBern. Spanning 62 chapters and a reference appendix, this book
After Ogden Bruton’s description of agammaglobulin- coversalltheimmunodeficienciesofthepreviouseditions
emia in 1952, American physicians dominated the field and many new disorders (cid:1) a total of nearly 200 different
for the next half-century, with descriptions of common disorders.
variable immunodeficiency, DiGeorge syndrome, SCID This edition also represents a first for electronic pub-
syndromes, complement defects, and chronic granuloma- lishing for this specialty. This technology will expand the
tousdisease. accessibility of the book and make instant retrieval of
Thus, the editors of the first edition suggested that an informationareality.
appropriate subtitle could be “A Tale of Two Cities,” KathleenSullivan
paying homage to Robert Good of Minneapolis (and E.RichardStiehm
Stiehm’sImmuneDeficienciesisaccompaniedbyawebsitefeaturingarangeofvideosrelevanttothisbook.
Toaccessthesecompanionresources,pleasevisithttp://booksite.elsevier.com/9780124055469/
xv
Acknowledgments
The editors thank Dawn Westerfer of the Children’s contribution. We also acknowledge the importance of our
Hospital of Philadelphia for her editorial assistance, and colleagues and Associate Editors Luigi Notarangelo,
ourfamiliesandourpatients. Thepatientsarethe founda- Charlotte Cunningham-Rundles, Steven Holland, and
tionofallthatwedoandweacknowledgetheirimportant AlainFischer.
xvii
List of Contributors
Mark Ballow, Department of Pediatrics, University of Mount Sinai School of Medicine, New York, NY,
South Florida School of Medicine, All Children’s USA
Hospital, Division of Allergy & Immunology, Rebeca Pe´rez de Diego, Department of Immunology,
St Petersburg, Florida, USA; Division of Allergy/
IdiPAZ Institute for Health Research, La Paz
Clinical Immunology and Pediatric Rheumatology,
UniversityHospital,Madrid,Spain
Department of Pediatrics, SUNY Buffalo School of
Adriana A. de Jesus, Translational Autoinflammatory
Medicine and Biomedical Sciences, Buffalo, New
Disease Section, National Institute of Arthritis,
York,USA
Musculoskeletal and Skin Diseases, National Institutes
Mohamed-RidhaBarbouche, DepartmentofImmunology,
ofHealth,Bethesda,MD,USA
Institut Pasteur de Tunis and Medical School, University
Genevie`ve de Saint Basile, INSERM, Hoˆpital Necker
ofTunis,Tunis,Tunisia
Enfants-Malades; Universite´ Paris Descartes-Sorbonne
Vincent R. Bonagura, Center for Immunology and Paris Cite´, Institut Imagine; and Unite´ d’Immunologie
Inflammation, The Feinstein Institute for Medical et He´matologie Pe´diatrique, et Centre d’Etudes des
Research, Manhasset, New York, NY, USA; and De´ficits Immunitaires, Assistance Publique-Hoˆpitaux
Department of Pediatrics and Molecular Medicine, de Paris, Hoˆpital Necker Enfants-Malades, Paris,
Hofstra North Shore-LIJ School of Medicine, Great
France
Neck,NewYork,NY,USA
Esther de Vries, Department of Paediatrics, Jeroen
Francisco A. Bonilla, Boston Children’s Hospital, and
BoschHospital,s-Hertogenbosch,TheNetherlands
HarvardMedical School,Boston,Massachusetts,USA
Inderjeet Dokal, Centre for Paediatrics, Blizard
Sarah K. Browne, Laboratory of Clinical Infectious
Institute, Barts and The London School of Medicine
Diseases, National Institute of Allergy and Infectious
and Dentistry, Queen Mary University of London,
Diseases, National Institutes of Health, Bethesda,
BartsHealth,London,UK
Maryland,USA
Anne Durandy, Centre d’e´tude des de´ficits immuni-
Fabio Candotti, Disorders of Immunity Section, Genetics taires, Hoˆpital Necker Enfants Malades, Paris, France;
and Molecular Biology Branch National Human Institut National de la Sante´ et de la Recherche
GenomeResearchInstitute,NationalInstitutesofHealth, Me´dicale U768, Hoˆpital Necker Enfants Malades,
Bethesda,MA,USA
Paris,France
Magda Carneiro-Sampaio, Faculdade de Medicina da Stephan Ehl, University Medical Center Freiburg,
UniversidadedeSa˜oPaulo,Brazil Center of Chronic Immunodeficiency, Freiburg,
Talal A. Chatila, Division of Immunology, The Boston Germany
Children’s Hospital, Department of Pediatrics, Harvard Robert Eisenberg, Department of Medicine, University
MedicalSchool,Boston,MA,USA ofPennsylvania,Philadelphia,PA,USA
Yanick J. Crow, Genetic Medicine, Institute of Human Brian Eley, Paediatric Infectious Diseases Unit, Red
Development, Faculty of Medical and Human Sciences, Cross War Memorial Children’s Hospital, and the
University of Manchester; and St Mary’s Hospital, Department of Paediatrics and Child Health,
CentralManchesterUniversityHospitalsNHSFoundation UniversityofCapeTown,CapeTown,SouthAfrica
Trust, Manchester Academic Health Science Centre,
Amos Etzioni, Department of Pediatrics and
Manchester,UK
Immunology, Ruth Rappaport Children’s Hospital,
Charlotte Cunningham-Rundles, Departments of Rambam Health Campus, Haifa; and Faculty of
Medicine and Pediatrics, The Immunology Institute, Medicine,Technion,Haifa,Israel
xix
xx ListofContributors
Polly J. Ferguson, University of Iowa Carver College of Suheir Hanna, Department of Pediatrics and
Medicine, Department of Pediatrics, Iowa City, IA, Immunology, Ruth Rappaport Children’s Hospital,
USA Rambam Health Campus, Haifa; and Faculty of
Thomas A. Fleisher, Laboratory of Host Defenses, Medicine,Technion,Haifa,Israel
Department of Laboratory Medicine, National Steven M. Holland, Laboratory of Clinical Infectious
Institutes of Health Clinical Center, NIH, Bethesda, Diseases, National Institute of Allergy and Infectious
MD,USA Diseases, National Institutes of Health, Bethesda,
Maryland,USA
Michael M. Frank, Department of Pediatrics, Medicine
and Immunology, Duke University Medical Center, de Villartay Jean-Pierre, INSERM, Hoˆpital Necker-
Durham,NorthCarolina,USA Enfants Malades, Unite´ De´veloppement Normal et
PathologiqueduSyste`meImmunitaire,Paris,France
Alexandra F. Freeman, Laboratory of Clinical
Infectious Diseases, National Institute of Allergy and Sara Kashef, Department of Immunology & Infectious
Infectious Diseases, National Institutes of Health, Diseases, Sydney Children’s Hospital, Randwick, New
Bethesda,Maryland,USA South Wales, Australia; Department of Pediatrics,
ShirazUniversityofMedical Sciences,Shiraz,Iran
Eleonora Gambineri, Department of NEUROFARBA,
Christoph Klein, Department of Pediatrics, Dr von
University of Florence; and Department of
Hauner Children’s Hospital, Ludwig-Maximilians-
Haematology-Oncology, and Department of Fetal and
Neonatal Medicine, Anna Meyer Children’s Hospital, UniversityMunich,Munich,Germany
Florence,Italy Donald B. Kohn, Department of Microbiology,
Immunology & Molecular Genetics, and Department of
Benjamin Gathmann, Center for Chronic
Pediatrics (Hematology/Oncology), Mattel Children’s
Immunodeficiency, University Medical Center
Hospital, David Geffen School of Medicine, University
FreiburgandUniversityofFreiburg,Germany
ofCalifornia,LosAngeles,California,USA
Raif S. Geha, Boston Children’s Hospital, Immunology
Sven Kracker, Faculte´ de Medicine Descartes-Sorbonne
Division,Boston,Massachusetts,USA
Paris Cite´, Universite´ de Paris, Institut Imagine, Paris,
Andrew R. Gennery, Department of Paediatric France; Institut National de la Sante´ et de la
Immunology and Haematopoietic Stem Cell Recherche Me´dicale U768, Hoˆpital Necker Enfants
Transplantation, Institute of Cellular Medicine, Malades,Paris,France
NewcastleUniversity,NewcastleuponTyne,UK
Yu-Lung Lau, Department of Paediatrics and
Erik-Oliver Glocker, Department of Medical Adolescent Medicine, Li Ka Shing Faculty of
Microbiology and Hygiene, Institute of Medical Medicine, The University of Hong Kong, Hong Kong
Microbiology and Hygiene, University Medical Center SpecialAdministrativeRegion,China
Freiburg,Freiburg,Germany
Pamela Lee, Department of Paediatrics and Adolescent
Raphaela Goldbach-Mansky, Translational Auto- Medicine, Li Ka Shing Faculty of Medicine, The
inflammatory Disease Section, National Institute of University of Hong Kong, Hong Kong Special
Arthritis, Musculoskeletal and Skin Diseases, National AdministrativeRegion,China
InstitutesofHealth,Bethesda,MD,USA
Heather Lehman, Division of Allergy/Clinical
John M. Graham, Jr, Medical Genetics Institute, Immunology and Pediatric Rheumatology, Department
Cedars-Sinai Medical Center, Department of of Pediatrics, SUNY Buffalo School of Medicine and
Pediatrics, David Geffen School of Medicine at Biomedical Sciences, Buffalo, New York, USA;
UCLA,LosAngeles,CA,USA Women & Children’s Hospital of Buffalo, Buffalo,
Bodo Grimbacher, Center for Chronic Immuno- NewYork,USA
deficiency, University Medical Center Freiburg and Jennifer W. Leiding, Division of Allergy, Immunology,
UniversityofFreiburg,Germany and Rheumatology, University of South Florida, St
Elie Haddad, Pediatric Immunology and Rheumatology Petersburg,Florida,USA
Division,CHUSainte-Justine,DepartmentofPediatrics, Lily E. Leiva, Department of Pediatrics and Jeffrey
UniversityofMontreal,Montreal,QC,Canada Modell Center for Immunodeficiencies, Louisiana
Sophie Hambleton, Institute of Cellular Medicine, State University Health Science Center, New Orleans,
Newcastle University and Great North Children’s LA,USA
Hospital,NewcastleuponTyne,UK
ListofContributors xxi
Michael J. Lenardo, Laboratory of Immunology, Hans Ochs, Pediatric Immunology, University of
National Institute of Allergy and Infectious Diseases, Washington and Seattle Children’s Hospital, Seattle,
NationalInstitutesofHealth,Bethesda,MD,USA WA,USA
Arnold I. Levinson, Pulmonary Allergy and Critical Joa˜o Bosco Oliveira, Instituto de Medicina Integral
Care Division, Perelman School of Medicine, ProfessorFernandoFigueira,Recife,Brazil
UniversityofPennsylvania,Philadelphia,PA,USA Jordan S. Orange, Baylor College of Medicine, and
Robert Y. Lin, Department of Medicine, Weill Cornell DepartmentofImmunology,Allergy,andRheumatology,
MedicalCenter,NewYork,NY,USA TexasChildren’sHospital,Houston,Texas,USA
Vassilios Lougaris, Pediatrics Clinic and Institute of RobertoPaganelli, DepartmentofMedicineandSciences
Molecular Medicine “A. Nocivelli,” Department ofAging,UniversityG.d’Annunzio,Chieti,Italy
of Clinical and Experimental Sciences, University of
Graham Pawelec, Second Department of Internal
Brescia,SpedaliCivilidiBrescia,Italy
Medicine, University of Tu¨bingen Medical School,
M. Louise Markert, Duke University Medical Center, Tu¨bingen,Germany
Durham,NorthCarolina,USA
Elena E. Perez, University of Miami, Department of
Rebecca A. Marsh, Division of Bone Marrow Pediatrics,Miami,Florida,USA
Transplantation and Immune Deficiency, Cincinnati
Alessandro Plebani, Pediatrics Clinic and Institute of
Children’sHospital,Cincinnati,OH,USA
Molecular Medicine “A. Nocivelli,” Department
La´szlo´ Maro´di, Department of Infectious and Pediatric of Clinical and Experimental Sciences, University of
Immunology, Faculty of Medicine, University of Brescia,SpedaliCivilidiBrescia,Italy
Debrecen,Debrecen,Hungary
Oscar Porras, Pediatric Immunology and Rheumatology
David H. McDermott, Laboratory of Molecular Department, National Children(cid:1)s Hospital, San
Immunology, National Institute of Allergy and Jose´, Costa Rica; University of Costa Rica,
Infectious Diseases, National Institutes of Health, Costa Rica; and University of Iberoamerica, Costa
Bethesda,Maryland,USA Rica
Douglas R. McDonald, Division of Immunology, Jennifer M. Puck, Department of Pediatrics and
Children’s Hospital and Department of Pediatrics, Institute for Human Genetics, University of California
HarvardMedical School,Boston,Massachusetts,USA San Francisco and UCSF Benioff Children’s Hospital,
Stephen J. McGeady, Jefferson Medical College, SanFrancisco,CA,USA
Thomas Jefferson University, Philadelphia, PA, USA, Isabella Quinti, Department of Experimental Medicine,
and Division of Allergy and Immunology, Alfred I. UniversityLaSapienza,Rome,Italy
duPontHospitalforChildren,Wilmington,DE,USA
Nima Rezaei, Research Center for Immunodeficiencies,
Joshua D. Milner, Laboratory of Allergic Diseases,
Children’s Medical Center; and Department of
National Institute of Allergy and Infectious Diseases,
Immunology, School of Medicine, Tehran University
National Institutes of Health, Bethesda, MD, USA
ofMedicalSciences,Tehran,Iran
Jeffrey E. Ming, Department of Pediatrics, Division of
Carlos Rodr´ıguez-Gallego, University of Las Palmas
Human Genetics, The Children’s Hospital of
de Gran Canaria, School of Medicine, and
Philadelphia and the University of Pennsylvania
Department of Immunology, Gran Canaria Dr. Negr´ın
SchoolofMedicine,Philadelphia,PA,USA
University Hospital, Las Palmas de Gran Canaria,
Despina Moshous, INSERM, Hoˆpital Necker-Enfants Spain
Malades, Unite´ De´veloppement Normal et
Sergio D. Rosenzweig, Laboratory of Host Defenses,
PathologiqueduSyste`meImmunitaire,Paris,France
Department of Laboratory Medicine, National
Ludmila Mu¨ller, Max Planck Institute for Human Institutes of Health Clinical Center, National Institutes
Development,Berlin,Germany ofHealth,Bethesda,Maryland,USA
Kim E. Nichols, Division of Oncology, Children’s John M. Routes, Medical College of Wisconsin,
HospitalofPhiladelphia,Philadelphia,PA,USA Milwaukee,Wisconsin,USA
Luigi D. Notarangelo, Division of Immunology, Irini Sereti, Laboratory of Immunoregulation, National
Children’s Hospital Boston, Harvard Stem Cell Institute of Allergy and Infectious Diseases, National
Institute, Harvard Medical School, Harvard, InstitutesofHealth,Bethesda,MD,USA
Cambridge,MA,USA
Ricardo U. Sorensen, Department of Pediatrics and
Jeffrey Modell Center for Immunodeficiencies,
xxii ListofContributors
Louisiana State University Health Science Center, James W. Verbsky, Division of Rheumatology,
NewOrleans,LA,USA Department of Pediatrics, Medical College of
Carsten Speckmann, Center for Pediatrics and Wisconsin,Milwaukee,WI,USA
Adolescent Medicine, Center of Chronic Anna Villa, Human Genome Department, Milan Unit,
Immunodeficiency, University Medical Center Freiburg, Genetic and Biomedical Research, Consiglio
Freiburg,Germany NazionaledelleRicerche,Milan,Italy
Helen C. Su, Laboratory of Host Defenses, National Klaus Warnatz, University Medical Centre Freiburg,
Institute of Allergy and Infectious Diseases, National Centre of Chronic Immunodeficiency, Division of
InstitutesofHealth,Bethesda,MD,USA Rheumatology and Clinical Immunology, Freiburg,
Kathleen E. Sullivan, University of Pennsylvania Germany
Perelman School of Medicine, The Children’s Hospital Corry M.R. Weemaes, Department of Pediatric
ofPhiladelphia,Philadelphia,Pennsylvania,USA Infectious Disease and Immunology, Radboud
M. Teresa de la Morena, Division of Allergy and UniversityNijmegenMedical Centre,TheNetherlands
Immunology, University of Texas Southwestern Hale Yarmohammadi, The Icahn School of Medicine at
Medical Center in Dallas at Children’s Medical Center MountSinai,NewYork,NY,USA
Dallas,Dallas,TX,USA Joyce E. Yu, Department of Pediatrics, Division of
Troy Torgerson, Pediatric Immunology/Rheumatology, Allergy & Immunology, Morgan Stanley Children’s
University of Washington and Seattle Children’s Hospital of New York-Presbyterian, Columbia
Hospital,Seattle,WA,USA UniversityMedicalCenter,NewYork,NY,USA
James Treat, University of Pennsylvania Perelman John B. Ziegler, Department of Immunology &
School of Medicine, The Children’s Hospital of Infectious Diseases, Sydney Children’s Hospital,
Philadelphia,Philadelphia,Pennsylvania,USA Randwick,NewSouthWales,Australia
Mirjam van der Burg, Department of Immunology, Heddy Zola, Women’s and Children’s Health Research
Erasmus MC, University Medical Center Rotterdam, Institute and Discipline of Paediatrics, University of
Rotterdam,TheNetherlands Adelaide,Adelaide,SA,Australia.
Silve`re M. van der Maarel, Department of Human
Genetics, Leiden University Medical Center Leiden,
TheNetherlands
Chapter 1
Common Presentations and
Diagnostic Approaches
NimaRezaei1,EstherdeVries2,EleonoraGambineri3,andElieHaddad4
1ResearchCenterforImmunodeficiencies,Children’sMedicalCenter;andDepartmentofImmunology,SchoolofMedicine,TehranUniversityof
MedicalSciences,Tehran,Iran,2DepartmentofPaediatrics,JeroenBoschHospital,s-Hertogenbosch,TheNetherlands,3Departmentof
NEUROFARBA,UniversityofFlorence;andDepartmentofHaematology-Oncology,andDepartmentofFetalandNeonatalMedicine,AnnaMeyer
Children’sHospital,Florence,Italy,4PediatricImmunologyandRheumatologyDivision,CHUSainte-Justine,DepartmentofPediatrics,University
ofMontreal,Montreal,QC,Canada
ChapterOutline
PrevalenceandDemographics 3 Candida 22
RecurrentInfections 11 Aspergillus 23
Recurrent“Normal”Infections 11 Gram-NegativeRods 24
Recurrent“Abnormal”Infections 12 CutaneousInfections 25
SentinelInfections 13 ChronicDiarrhea 27
HerpesSimplexEncephalitis 13 ShortStaturewithInfections 29
Epstein-BarrVirus 14 Malignancies 37
Cytomegalovirus 15 Neutropenia 40
PapillomaVirus(Warts) 17 References 42
Mycobacterium 20
PREVALENCE AND DEMOGRAPHICS For educational, clinical, and research purposes,
classification of PIDs is of paramount importance. The
Primary immune deficiencies (PIDs) form a heteroge-
Expert Committee of the International Union of
neous group of inherited disorders, generally caused by
Immunological Societies (IUIS) classified PIDs into eight
specific gene mutations affecting immune system general categories in terms of immune defect.3 Table 1.1
development and function.1 PIDs can be characterized by
summarizesthePIDsthataredescribedinthisbook.
various clinical manifestations, ranging from asymptom-
Worldwide, several national and international regis-
atic immune disorders to diseases associated with
tries have been established to identify patients with PID
severe infections, autoimmunity, and malignancies.1
in order to improve timely diagnosis and management.
Descriptions of PIDs date back to more than six decades
Moreover, these registries help to estimate the global
ago, when Dr Bruton described X-linked agammaglobu-
prevalence and burden of PIDs. To date, more than 50
linemia (XLA) in 1952.2 In the intervening time, about
national registries across different continents are active.
200 disorders have been identified, and their number is
The European Society for Immune Deficiencies (ESID),
still growing rapidly.3 The first description of PID was
the Latin American Group for Primary Immunodeficiency
largely due to the discovery of antibiotics that revolu-
Diseases (LAGID), and the NorthAfrica Registry provide
tionized care of severe infections in normal subjects, but
data from several countries mostly located in correspond-
not significantly in a subgroup with immune deficiencies. ing regions.5(cid:1)7 Considering the last reports of registries
Since then, progress in genetics and molecular biology of the ESID in April 2013, the LAGID in 2007,5 the
has contributed to our understanding.1,4
United States Immune Deficiency Network (USIDNET)
K.E.SullivanandE.R.Stiehm(Eds):Stiehm’sImmuneDeficiencies.DOI:http://dx.doi.org/10.1016/B978-0-12-405546-9.00001-7
©2014ElsevierInc.Allrightsreserved. 3
