Pediatric Immunology. A Case-Based Collection with MCQs [Volume 2] 9783030212612, 9783030212629

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Pediatric Immunology A Case-Based Collection with MCQs, Volume 2 Nima Rezaei Editor

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Pediatric Immunology

Nima Rezaei Editor

Pediatric Immunology A Case-Based Collection with MCQs, Volume 2

Editor Nima Rezaei Department of Immunology, School of Medicine Research Center for Immunodeficiencies (RCID) Children’s Medical Center Tehran University of Medical Sciences (TUMS) Tehran Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA) Universal Scientific Education and Research Network (USERN) Tehran Iran

ISBN 978-3-030-21261-2    ISBN 978-3-030-21262-9 (eBook) https://doi.org/10.1007/978-3-030-21262-9 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Immunology has found its way well into the practice of pediatrics. Years after publication of the first pediatric textbooks, foot prints of immunology can be found in diagnosis and practice of almost all pediatric disorders. Delivering a magnificent contribution is the advent of novel diagnostic methods in molecular genetics in pediatric practice. Genetic diagnosis is now an indispensable part of the routine practice of primary immunodeficiency disorders, inborn metabolic errors, and monogenic malformations, making way into diagnostic criteria of some as well. It won’t go far wrong to state that the science of pediatrics has entered into an era of interdisciplinary practice with genetics and immunology. The rapid flow of discovery of biological drugs during the last decade, availability of next-genome and whole-exome sequencing methods, and the outstanding boost in the rate of success of hematopoietic and solid organ transplantation are all affirmative to this notion. Thanks to molecular genetic methods, an increasing number of the newly introduced “autoinflammatory disorders” are being characterized, donors and recipients are being cross-matched using intricate genotype:phenotype cross matching, and immunotherapy for allergy benefits from state-of-the-art characterization of culprit epitopes in peptide scales. This book tries to strike a balance between cutting-edge science of immunology and clinical practice of pediatrics, through a series of meticulously chosen case discussions, presented by pediatric practitioners and immunology experts. Pediatric Immunology Series is a three-volume book series and a collection of well-presented case discussions in pediatric medicine. Volume I, Pediatric Allergy, is focused on diagnosis and practice of allergy, asthma, atopy, and relevant disorders. Volume II, Pediatric Immunology, thoroughly addresses cases on primary immunodeficiency disorders; and finally, Volume III, Pediatric Autoimmunity and Transplantation, is a constellation of cases in autoimmune and rheumatologic disorders of childhood, secondary immunodeficiency conditions, and real cases with hematopoietic and solid organ transplantation. Volume II of this series is a comprehensive guide to the essentials of diagnosis and practice of primary immunodeficiency disorders (PID). Covering all groups of PIDs, the book starts with Chaps. 2–24, and 25 on humoral immunodeficiency, v

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Preface

Chaps. 25–49, and 50 on combined immunodeficiency, Chaps. 51–65, and 66 on phagocyte defects, and Chaps. 67–74, and 75 on innate immunity defects. By this far in the book the reader has already gained a head start on four of the five classic types of PID, continued by Chaps. 114–121, and 122 presenting patients with complement system defects. Immune dysregulation disorders and autoinflammatory disorders are on the other facet of the coin of PID disorders and are presented in Chaps. 76–112, and 113, respectively. Chapters 123–146, and 147 comprise the final frame of this volume, with case-based discussions on a new and fast-­growing domain of PIDs: PIDs associated with syndromic features. The Pediatric Immunology Series is the result of a multinational collaboration of more than 350 scientists from more than 100 well-known universities/institutes worldwide. I would like to hereby acknowledge the expertise of all contributors, for their generous devotion of time and effort in preparing each of the chapters. I would like to extend my gratitude to Springer publication for providing me the opportunity to publish the book. Hopeful I remain, that this book provides an exemplary touch to the fast-growing intersection of pediatric medicine and basic immunology, and a useful guide for pediatric practitioners worldwide. Tehran, Iran  Nima Rezaei

Acknowledgments

I would like to express my sincere gratitude for the tremendous efforts of my Editorial Assistant, Dr. Farzaneh Rahmani. I would like to gratefully acknowledge her fine work, without which completion of this book would not have been possible. Nima Rezaei

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Abbreviations

4CmenB 4-Component meningococcal serogroup B vaccine ACE Angiotensin-converting enzyme AD Autosomal dominant ADA Adenosine deaminase ADHD Attention-deficit hyperactivity disorder AD-HIES Autosomal dominant hyper-IgE syndrome AFP Alpha-fetoprotein AID Activation-induced deaminase AIDS Acquired immunodeficiency syndrome AIFEC Autoinflammation with infantile enterocolitis AIHA Autoimmune hemolytic anemia AIN Autoimmune neutropenia AIRE Autoimmune regulator AKI Acute kidney injury ALL Acute lymphoblastic leukemia ALPS Autoimmune lymphoproliferative syndrome AML Acute myeloid leukemia ANC Absolute neutrophil count Anti-CCP Anti-cyclic citrullinated peptide Anti-dsDNA Anti-double-stranded DNA APC Antigen-presenting cells APDS1 Activated phosphoinositide 3-kinase δ syndrome type 1 APDS2 Activated phosphoinositide 3-kinase δ syndrome type 2 APECED Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy APGAR Appearance, pulse, grimace, activity, and respiration APS-1 Autoimmune polyendocrine syndrome type 1 AR Autosomal recessive AR-HIES Autosomal recessive hyper-IgE syndrome array CGH, aCGH Microarray-based comparative genomic hybridization A-T Ataxia-telangiectasia ix

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AT1R ATG ATR BCG BD BLNK BMT BP bpm BSA BTK C1-INH C3c c-ANCA CARD9 CAT CBC CD CD40L CDC CDCA7 CECR1 CF CFTR CGD CHS CID CINCA

Abbreviations

Anti-angiotensin II type 1 receptor Anti-thymocyte globulin Ataxia-telangiectasia and Rad3 related Bacillus Calmette–Guérin (BCG) Behçet’s disease B cell linker protein Bone marrow transplantation Blood pressure Beats per minute Body surface area Bruton’s tyrosine kinase C1 esterase inhibitor C3 convertase Cytosolic anti-neutrophil cytoplasmic antibodies Caspase recruitment domain family member 9 Cutaneous assessment tool Complete blood count Cluster of differentiation CD40 ligand Complement-dependent cytotoxicity Cell division cycle-associated protein 7 Cat eye syndrome chromosome region 1 Cystic fibrosis Cystic fibrosis transmembrane conductance regulator Chronic granulomatous disease Chediak-Higashi syndrome Combined immunodeficiency Chronic infantile neurological and cutaneous articular syndrome CK Creatine kinase CK-MB Creatine kinase-MB CLD Chronic lung disease CLR Clarithromycin CMC Chronic mucocutaneous candidiasis CML Chronic myeloid leukemia CMV Cytomegalovirus CNO Chronic non-bacterial osteomyelitis Con-A Concanavalin A CRMO Chronic recurrent multifocal osteomyelitis CRP C-reactive protein CS Cogan’s syndrome CsA Cyclosporine A CSF Cerebrospinal fluid CSR Class-switch recombination CT Computed tomography

Abbreviations

CTL CVID CXCR4 CXR DADA2 DAT DCLRE1C DDS DHR DIC DIF DIRA DNA DNT DOCK8 DSB dsDNA DT dT

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Cytotoxic T lymphocytes Common variable immune deficiency CXC chemokine receptor 4 Chest X-ray Deficiency of adenosine deaminase type-2 Direct antibody test DNA cross-link repair protein 1C Deafness-dystonia-optic neuropathy syndrome Dihydrorhodamine test Dsseminated intravascular coagulation Direct immunofluorescence Deficiency of interleukin-1 receptor antagonist Deoxyribonucleic acid Double negative T cells Dedicator of cytokinesis 8 Double-strand breaks Double-stranded DNA autoantibodies Diphteria and tetanus toxoids full strength Diphtheria-tetanus toxoids with reduced content of diphtheria DtaP Diphtheria-tetanus acellular pertussis vaccine DTaP3 Diphtheria-tetanus-3-component acellular pertussis vaccine DTaP5-IPV-Hib Diphtheria-tetanus-3-component acellular pertussis-­ inactivated polio-haemophilus influenzae type b" DTaP-IPV-HBV+Hib Hexavalent diphteria-tetanus-acellular pertussis-­ inactivated polio-hepatitis B vaccine EBV Epstein-Barr virus EDA Anhidrotic ectodermal dysplasia EDA-ID Anhidrotic ectodermal dysplasia and immunodeficiency EGPA Eosinophilic granulomatosis with polyangiitis ELANE Neutrophil elastase ELE Erysipelas-like erythema ELISA Enzyme-linked immunosorbent assay EMG Electromyography ENA Anti-extractable nuclear antigens panel ERK Extracellular signal regulated kinases ES Evans syndrome ESBL Extended spectrum beta lactamase positive E. coli ESID European Society for Immunodeficiencies ESR Erythrocyte sedimentation rate EULAR European League Against Rheumatism FADD Fas-associated death domain Fas First apoptosis signal FCAS Familial cold autoimmune syndrome

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Abbreviations

FCAS4 Familial cold autoinflammatory syndrome 4 FDA Food and Drug Administration FEV1 Forced expiratory volume in 1 second FFP Fresh frozen plasma FHLH Familial HLH FHLH/FHL Familial hemophagocytic lymphohistiocytosis FIA Flow injection analysis FIM Fulminant infectious mononucleosis FISH Fluorescence in situ hybridization Flt3L Fms-like tyrosine kinase 3 ligand FMF Familial Mediterranean fever FOXP3 Forkhead box protein 3 FPD Familial platelet disorder FPD/AML FPD with predisposition to AML FTT Failure to thrive G6PC3 Glucose-6-phosphatase catalytic subunit 3 G6PD Glucose-6-phosphatase deficiency GATA2 GATA-binding factor 2 G-CSF Granulocyte colony stimulating factor GI Gastrointestinal GLILD Granulomatous-lymphocytic interstitial lung disease GM-CSF Granulocyte, monocyte colony stimulating factor GOF Gain-of-function GPA Granulomatosis with polyangiitis GPCR G protein-coupled receptor GS Griscelli syndrome GS2 Griscelli type 2 GU Genitourinary GVHD Graft versus host disease HAE Hereditary angioedema HAX1 HS-1-associated protein X-1 Hb Hemoglobin HBV Hepatitis B virus HCT Hematopoietic cell transplantation HCV Hepatitis C virus HDM House dust mite HELLS Helicase, lymphoid-specific Hib Haemophilus influenza type b vaccine HIDS Hyper-IgD syndrome HIES Hyper-IgE syndrome HIGM Hyper-IgM syndrome HIV Human immunodeficiency virus HLA Human leukocyte antigens HLA-B27 Human leukocyte antigen-B27 HLH Hemophagocytic lymphohistiocytosis

Abbreviations

HPS HPS2 HPV HRCT HSC HSCT HSE HSP HSV HUS IBD ICF

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Hermansky-Pudlak syndrome Hermansky-Pudlak type 2 Human papilloma virus High resolution computed tomography Hematopoietic stems cells Hematopoietic stem cell transplantation Herpes simplex encephalitis Henoch-Schönlein purpura Herpes simplex virus Hemolytic uremic syndrome Inflammatory bowel disease Immunodeficiency with centromeric instability and facial anomalies ICU Intensive care unit IDR score Immunodeficiency-related score IFI Invasive fungal infection IFN Interferon IFN-γ Interferon-γ IgA Immunoglobulin A IgE Immunoglobulin E IgG Immunoglobulin G IGHM mu variant of heavy chain of immunoglobulins IgM Immunoglobulin M IGRA Interferon-γ release assays IIV Inactivated influenza vaccine IkB Inhibitor of NF-κB IL Interleukin IL-12 Interleukin-12 ILD Interstitial lung disease IM Intramuscular IMIg Intramuscular injections of immunoglobulin Inf Influenza vaccine INH Isoniazide INO80 DNA helicase INO80 IP Incontinentia pigmenti IPEX Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome IPV Inactivated polio vaccine IRF-3 Interferon regulatory factor 3 ITK IL-2 inducible tyrosine/T-cell kinase ITP Idiopathic thrombocytopenic purpura IV Intravenous IVIG Intravenous immunoglobulin JAK Janus kinase JIA Juvenile idiopathic arthritis

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Abbreviations

JRA Juvenile rheumatoid arthritis KD Kawasaki disease kD Kilodalton Kg Kilogram KID Keratitis-ichthyosis-deafness KREC Kappa-deleting element recombination circle KS Kaposi sarcoma LAD Leukocyte adhesion deficiency LAIV Live attenuated influenza vaccine LDH Lactate dehydrogenase LE Lupus erythematosus LEKTI Kazal-type related inhibitor LFT Liver function test LOF Loss-of-function LRBA LPS-responsive beige-like anchor protein LRD Living related donor LTRAs Leukotriene receptor antagonists LTT Lymphocyte transformation test LYST Lysosome trafficking regulator protein MAC Membrane attack complex MAIT Mucosal associated invariant T cell MAPK Mitogen activated protein kinases MAS Macrophage activation syndrome MASP Mannose-binding lectin–associated serine proteases MBL Mannose-binding lectin MCV Mean corpuscular volume MDS Myelodysplastic syndrome MDS/AML Myelodysplastic syndrome/acute myeloid leukemia Men Meningococcal vaccine MenCV4 4-Valent (A,C,W-135,Y) conjugate meningococcal vaccine MFI Mean fluorescence intensity MHC Major histocompatibility complex MKD Mevalonate kinase deficiency MLPA Multiplex ligation PCR amplification MMA Methyl malonic acid MMF Mycophenolate mofetil mmHg Millimetre of mercury MMP8 and MMP9 Matrix metalloproteinase 8 and 9 MMR Measles-mumps-rubella MOTT Mycobacteria other than tuberculosis MPO Myeloperoxidase MRI Magnetic resonance imaging MRSA Methicillin-resistant Staphylococcus aureus MSH6 mutS homolog 6

Abbreviations

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MSMD Mendelian susceptibility to mycobacterial disease mTOR Mammalian target of rapamycin MTS Mohr-Tranebjaerg syndrome MUD Matched unrelated donors MVA Mevalonic aciduria NADPH Nicotinamide adenine dinucleotide phosphate NAT Nucleic acid testing NBS Nijmegen breakage syndrome NBT Nitroblue tetrazolium NEC Necrotizing enterocolitis NEMO NF-kB essential modulator NF-kB Nuclear factor kappa B NGS Next-generation sequencing NIH National Institute of Health NK cell Natural killer cell NKT cells Natural killer T cells NLRs NOD-like receptor NOMID Neonatal-onset multisystem inflammatory disease NSAIDs Nonsteroidal anti-inflammatory drugs NSDHL NAD(P) dependent steroid dehydrogenase-like NTM Non-tuberculous mycobacteria OCA Oculocutaneous albinism OL-EDA-ID Osteopetrosis, lymphedema and hemangiomas OPV Oral polio vaccine OS Omenn’s syndrome PACNS Primary angiitis of the central nervous system PAMPs and DAMPs Pathogen- and damage-associated molecular patterns PAN Polyarteritis nodosa p-ANCA Perinuclear anti-neutrophil cytoplasmic antibodies PAP Progressive pulmonary alveolar proteinosis PASLI p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency PBSCT Peripheral blood stem cell transplantation PCP Pneumocystis jirovecii pneumonia PCR Polymerase chain reaction PCV Pneumococcal conjugate vaccine PEG-ADA PEGylated ADA PFAPA Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis PFT Pulmonary function test PG Pyoderma gangrenosum PGD Preimplantation genetic diagnosis PHA Phytohemagglutinin PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase PI3KCD PI3K catalytic subunit delta isoform

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Abbreviations

PICU Pediatric intensive care unit PID Primary immunodeficiency disorder PMA Phorbol 12-myristate 13-acetate PMS2 Post-meiotic segregation increased 2 PO Per os/oral PPD Para-phenylenediamine PPSV Pneumococcal polysaccharide vaccine PRRs Pattern recognition receptors RA Rheumatoid arthritis RBC Red blood cell RF Rheumatoid factor RIF Rifabutin ROS Reactive oxygen species RSV Respiratory syncytial virus RSV-A Respiratory syncytial virus A RTE Recent thymic emigrants RV Rotavirus vaccine SAA Serum amyloid A SAD Specific antibody deficiency SAP SLAM-associated protein SCID Severe combined immunodeficiency SCIG Subcutaneous immunoglobulin SDF1 Stromal cell-derived factor 1 SDP Solvent detergent plasma SERPING1 Serpin family G member 1 SI Stimulation index SIGAD Selective IgA deficiency sIL-2R/sCD25 Soluble interleukin-2 receptor sIL-2Rα Soluble IL-2 receptor alpha SJIA Systemic juvenile idiopathic arthritis SLE Systemic lupus erythematosus SMA-II Spinal muscular atrophy type 2 SPINK5 Serine protease inhibitor, Kazal type 5 SSSS Staphylococcal scalded skin syndrome STAT3 Signal transducer and activator of transcription 3 STR Short tandem repeat SURFS Systemic undifferentiated recurring fever syndrome T Tetanus toxoid TACI Transmembrane activator and CAML interactor TCE T cell epitopes TCR T cell receptor TCRV T cell receptor variable chain TCRαβ Alpha/beta T cell receptor TCRγδ Gamma/delta T cell receptor TCS Topical corticosteroids TG Triglyceride

Abbreviations

Th1 Th17 Th2 THI TIA TIV TLRs TNFRSF13B TnT TORCH

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T helper 1 T helper 17 T helper 2 Transient hypogammaglobulinemia of infancy Transient ischemic attack Trivalent influenza vaccine Toll-like receptors Tumor necrosis factor receptor superfamily member 13B Troponin T Toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes TPN Total parenteral nutrition TRAF3 TNF receptor-associated factor 3 TRAPS TNF receptor-associated periodic syndrome TREC T cell receptor excision circles TRIF TIR domain-containing adaptor inducing IFN-β TSH Thyroid stimulating hormone TYK2 Tyrosine kinase 2 UA Urinary analysis UC Ulcerative colitis UNC-SAID or uSAID Unclassified systemic autoinflammatory disease UNG Uracil-DNA glycosylase UP Urticaria pigmentosa URI Upper respiratory tract infection V(D)J Variable, diversity, joining Var Varicella vaccine VUS Variants of unclear significance VZIG Varicella-zoster immune globulin VZV Varicella zoster virus WAS Wiskott-Aldrich syndrome WASp Wiskott-Aldrich syndrome protein WBC White blood cell WES Whole exome sequencing WGS Whole genome sequencing WHIM Warts, hypogammaglobulinemia, infections and myelokathexis XLA X-linked agammaglobulinemia XL-MDS X-linked myelodysplasia XLN X-linked neutropenia XLP X-linked lymphoproliferative disease XLP1 X-linked proliferative disorder type I XLT X-linked thrombocytopenia ZBTB24 Zinc-finger and BTB domain-containing 24 gene αβDNT Alpha/beta double negative T cells γc Common gamma chain γδDNT Gamma/delta double negative T cells

Contents

1 Introduction to Primary Immunodeficiencies ������������������������������������    1 Nima Rezaei, Soumya Pandey, Terry Harville, Anastasiia Bondarenko, Farzaneh Rahmani, Svetlana O. Sharapova, Per Wekell, Crescent Cossou-Gbeto, and Sevgi Köstel Bal 2 Workup of Recurrent Respiratory Infections and a Positive Family History����������������������������������������������������������������������������������������   13 Soumya Pandey and Terry Harville 3 Pseudomonas Meningitis ����������������������������������������������������������������������   15 Soumya Pandey and Terry Harville 4 Fever and Sleepiness������������������������������������������������������������������������������   21 Federica Pulvirenti and Isabella Quinti 5 Recurrent Pneumonia����������������������������������������������������������������������������   25 Ibtihal Benhsaien, Fatima Ailal, Jalila Bakkouri, and Ahmed Aziz Bousfiha 6 Developmental Regression��������������������������������������������������������������������   29 Juhee Lee 7 Recurrent Ear Infections and Pneumonia ������������������������������������������   33 Laura Marques, Lidia Branco, Julia Vasconcelos, and Esmeralda Neves 8 Positive Urine Culture for Klebsiella pneumoniae������������������������������   39 Sirje Velbri and Ülle Einberg 9 Brothers with Recurrent Sinopulmonary Infections and Chronic Lung Disease����������������������������������������������������������������������������   43 Anastasiia Bondarenko and Liudmyla Chernyshova

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10 Recurrent Infections and Arthritis������������������������������������������������������   49 Alla Volokha 11 Initial Diagnosis of Neutropenia and Later Crohn’s Disease������������   53 Soumya Pandey and Terry Harville 12 Diagnosis of “Sweat-Chloride Negative” Cystic Fibrosis������������������   59 Soumya Pandey and Terry Harville 13 Diagnosis of Sarcoidosis������������������������������������������������������������������������   63 Soumya Pandey and Terry Harville 14 Refractory Crohn’s disease ������������������������������������������������������������������   67 Soumya Pandey and Terry Harville 15 Asthma Which Was Not Asthma����������������������������������������������������������   71 Peter Jandus 16 Generalized Lymphadenopathy and Hypogammaglobulinemia After Abdominal Trauma����������������������������������������������������������������������   79 Omar K. Alkhairy, Abduarahman Almutairi, and Reem Walid Mohammed 17 Weakness and Anemia ��������������������������������������������������������������������������   85 Anastasiia Bondarenko 18 Normal Primary Care Workup for Recurrent Sinopulmonary Infections ��������������������������������������������������������������������   91 Soumya Pandey and Terry Harville 19 Recurrent Sinusitis and Persistent Giardia Infection������������������������   97 Taher Cheraghi 20 Recurrent Respiratory Infections��������������������������������������������������������  101 Markova Tatyana and Chuvirov Denis 21 Siblings Presenting with Mild and Severe Lymphoproliferation������  105 Olga Pashchenko, Irina Kondratenko, and Svetlana Vakhlyrskaya 22 Non-Malignant Lymphoproliferation��������������������������������������������������  109 Irina Kondratenko, Olga Pashchenko, and Andrey Bologov 23 Portal Hypertension and Progressive Lymphoproliferation��������������  115 Svetlana O. Sharapova 24 Recurrent Otitis and Upper Airway Obstruction ������������������������������  119 Narges Eslami, Mehrnaz Mesdaghi, and Zahra Chavoshzadeh 25 Recurrent Pneumonia����������������������������������������������������������������������������  123 Narges Eslami, Mehrnaz Mesdaghi, and Zahra Chavoshzadeh 26 A Growing BCG Lesion������������������������������������������������������������������������  127 Kathleen E. Sullivan

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27 Respiratory Distress and Hypoxemia��������������������������������������������������  133 Laura Marques, Lidia Branco, Julia Vasconcelos, and Esmeralda Neves 28 A Boy with Burdened Family History, Candidiasis and Diarrhea����  139 Anastasiia Bondarenko 29 Failure to Thrive������������������������������������������������������������������������������������  143 Hamid Nawaz Tipu and Wayne Bainter 30 Recurrent Respiratory Infection and Hypereosinophilia ������������������  147 Ester Conversano, Stefano Amoroso, and Alberto Tommasini 31 Neonatal Jaundice and Leukopenia ����������������������������������������������������  153 Mojgan Kianiamin and Nima Rezaei 32 Microcephaly, Recurrent Infections and Failure to Thrive���������������  157 Mihaela Tatiana Bataneant 33 Widespread Erythema and Skin Desquamation ��������������������������������  163 Anastasiia Bondarenko and Liudmyla Chernyshova 34 Failure to Thrive, Rash and Fever��������������������������������������������������������  169 Aisha Ahmed and Jennifer Puck 35 Autoimmune Cytopenia������������������������������������������������������������������������  175 Olga Pashchenko, Irina Kondratenko, and Svetlana Vakhlyrskaya 36 Recurrent Respiratory Tract Infections����������������������������������������������  179 Hamid Nawaz Tipu and Wayne Bainter 37 Protracted Diarrhea and Hypogammaglobulinemia��������������������������  185 Metin Yusuf Gelmez, Yildiz Camcioglu, and Gunnur Deniz 38 Gingivitis and Recurrent Tonsillitis������������������������������������������������������  193 Suzan Çınar, Manolya Kara, and Gunnur Deniz 39 Respiratory Distress������������������������������������������������������������������������������  199 Soumya Pandey and Terry Harville 40 Intestinal Cryptosporidiosis������������������������������������������������������������������  205 Reem Walid Mohammed, Abduarahman Almutairi, and Omar K. Alkhairy 41 Shortness of Breath��������������������������������������������������������������������������������  209 Julia K. Sohn and Monica G. Lawrence 42 Pneumocystis jiroveci Pneumonia Without Failure to Thrive������������  215 Mihaela Tatiana Bataneant and Patricia Urtila 43 Recurrent Infections and CNS Vasculitis��������������������������������������������  221 Melissa Espinosa-Navarro, Gabriela López-Herrera, and Laura Berrón-Ruiz

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44 Recurrent Infections and Widespread Warts��������������������������������������  229 Victoria R. Dimitriades and Alexandra F. Freeman 45 Rash and Several Food Allergies����������������������������������������������������������  233 Sara Seghezzo and Morna Dorsey 46 Severe Atopic Disease and Infections ��������������������������������������������������  237 Sule Haskologlu and Aydan Ikinciogulları 47 Acute Mastoiditis ����������������������������������������������������������������������������������  241 Reem Walid Mohammed, Abduarahman Almutairi, and Omar K. Alkhairy 48 Chronic Papulovegetative Ulcer on Penis��������������������������������������������  245 Mahboubeh Mansouri 49 Fever After DPT Vaccination����������������������������������������������������������������  249 Svetlana O. Sharapova 50 Recurrent Bronchiolitis ������������������������������������������������������������������������  255 Sevgi Köstel Bal and Figen Doğu 51 Oral Ulcers and Candidiasis ����������������������������������������������������������������  259 Nima Rezaei 52 Neutropenia and Myelodysplasia ��������������������������������������������������������  265 Mihaela Tatiana Bataneant 53 Loss of Appetite and Neutropenia��������������������������������������������������������  271 Lauren A. Sanchez and Sandhya Kharbanda 54 Delayed Umbilical Cord Separation����������������������������������������������������  277 Alireza Shafiei 55 Recurrent Pneumonitis��������������������������������������������������������������������������  279 Stefano Amoroso, Ester Conversano, and Alberto Tommasini 56 Recurrent Sepsis, Leukocytosis and Bleeding Tendency��������������������  285 Narissara Suratannon and Pantipa Chatchatee 57 Maculopapular Rash on BCG Site ������������������������������������������������������  289 Salem H. Al-Tamemi 58 Recurrent Perianal Abscesses ��������������������������������������������������������������  293 Kathleen Y. Wang 59 Infected Hemangiomas��������������������������������������������������������������������������  301 Reem Walid Mohammed, Abduarahman Almutairi, and Omar K. Alkhairy 60 Recurrent Invasive Bacterial Infections����������������������������������������������  305 Anna Hilfanova, Dariia Osypchuk, and Anastasiia Bondarenko

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61 Cervical Lymphadenitis������������������������������������������������������������������������  309 Laura Marques, Lidia Branco, Julia Vasconcelos, and Esmeralda Neves 62 Failure to Thrive and Nasal Obstruction��������������������������������������������  315 Daniel Rodriguez, Michael E. Dunham, and Luke A. Wall 63 Inflammatory Bowel Disease and Frequent Skin Abscesses��������������  321 Samantha Swain and Victoria R. Dimitriades 64 Necrotizing Liver Granuloma��������������������������������������������������������������  327 Neslihan Edeer Karaca, Guzide Aksu, and Necil Kutukculer 65 Constrictive Aspergillosis Pericarditis ������������������������������������������������  333 Neslihan Edeer Karaca, Guzide Aksu, and Necil Kutukculer 66 Lung Abscess������������������������������������������������������������������������������������������  339 Joshua M. Dorn, Tamara C. Pozos, and Roshini S. Abraham 67 Lethargy in a Toddler����������������������������������������������������������������������������  343 Farzaneh Rahmani and Nima Rezaei 68 Recurrent Cold Suppurative Granulomatous Lymphadenitis����������  347 Giuliana Giardino, Emilia Cirillo, Vera Gallo, and Claudio Pignata 69 Repetitive Fistulizing Lymphadenopathy and Hematochezia ����������  353 Mahboubeh Mansouri 70 Twins with Recurrent Candida Infections������������������������������������������  359 Geneviève Genest, Moshe Ben-Shoshan, and Ciriaco A. Piccirillo 71 Recurrent Stomatitis and Upper Respiratory Tract Infections��������  365 Anastasiia Bondarenko 72 Oral Thrush and Onychomycosis��������������������������������������������������������  371 Giuliana Giardino, Emilia Cirillo, Vera Gallo, and Claudio Pignata 73 Oral Moniliasis and Failure to Thrive��������������������������������������������������  377 Ayca Kiykim and Safa Baris 74 Refractory Oral Thrush������������������������������������������������������������������������  383 Farzaneh Rahmani and Nima Rezaei 75 Kidney Malformation and Persistent Neutropenia����������������������������  387 Mihaela Tatiana Bataneant 76 Severe Pancytopenia������������������������������������������������������������������������������  395 Sarah Lena Maier and Kai Lehmberg 77 Silvery Hair��������������������������������������������������������������������������������������������  403 Edna Venegas-Montoya, Nancy Jimenez Polvo, and Sara Espinosa-Padilla

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78 Fever and Blonde Skin��������������������������������������������������������������������������  407 Javad Ghaffari 79 Probable Sepsis��������������������������������������������������������������������������������������  411 Javad Ghaffari 80 Skin Abscess and Blonde Hair��������������������������������������������������������������  413 Farzaneh Rahmani, Aziz Eghbali, and Nima Rezaei 81 Recurrent Infections and Easy Bruising����������������������������������������������  419 Nima Parvaneh 82 Fever and Skin Eruption ����������������������������������������������������������������������  423 Hirokazu Kanegane 83 Cervical Lymphadenopathy and Nasopharyngeal Mass��������������������  431 Daniel Rodriguez, Matthew Stark, and Luke A. Wall 84 Lymphadenopathy and Splenomegaly ������������������������������������������������  437 Joshua M. Dorn, Avni Y. Joshi, and Roshini S. Abraham 85 Anemia and Neutropenia����������������������������������������������������������������������  443 Kristin Shimano 86 Hemolytic Anemia and Lymphadenopathy ����������������������������������������  449 Svetlana O. Sharapova 87 Recurrent Infections and Chronic Diarrhea ��������������������������������������  453 Sevgi Kostel Bal and Aydan Ikinciogullari 88 Recurrent Infections, Cytopenias and Lung Disease��������������������������  459 Elizabeth Wisner and Victoria R. Dimitriades 89 Short Stature, Prolonged Fever and Lymphoproliferation����������������  463 Maria Kanariou, Sofia Tantou, and Kosmas Kotsonis 90 Siblings with Nail Dystrophy and Photophobia����������������������������������  469 Samin Sharafian 91 Chronic Diarrhea and Failure to Thrive����������������������������������������������  473 Sara Seghezzo, Kiran Patel, and Alice Y. Chan 92 Rash and Diarrhea��������������������������������������������������������������������������������  479 Anna R. Smith and Monica G. Lawrence 93 Recurrent Infections, Enteropathy and Granulomatous Lung Disease������������������������������������������������������������������������������������������  485 Sarah E. Henrickson and Kathleen E. Sullivan 94 Chronic Diarrhea ����������������������������������������������������������������������������������  491 Nasrin Behniafard and Majid Aflatoonian

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95 Early-Onset Inflammatory Bowel Disease������������������������������������������  495 Neslihan Edeer Karaca, Guzide Aksu, and Necil Kutukculer 96 Recurrent Febrile Episodes and Abdominal Pain������������������������������  501 Per Wekell, Stefan Berg, and Anders Fasth 97 Episodic Fever and Lymphadenopathy������������������������������������������������  511 Romina Dieli-Crimi and Theresa Español 98 Periodic Fever Syndrome and Developmental Delay��������������������������  515 Per Wekell, Stefan Berg, and Anders Fasth 99 Periodic Fever and Maculopapular Rash��������������������������������������������  521 Yuriy Stepanovskiy 100 Long Episodes of Rash and Fever��������������������������������������������������������  527 Stefan Berg, Anders Fasth, and Per Wekell 101 Long-Lasting History of Urticaria ������������������������������������������������������  533 Sergio Ghirardo, Alberto Tommasini, and Andrea Taddio 102 Rash and Fever since Two Weeks of Age����������������������������������������������  539 Stefan Berg, Anders Fasth, and Per Wekell 103 Aseptic Meningitis����������������������������������������������������������������������������������  545 Peter Jandus 104 Recurrent Fever and Sore Throat��������������������������������������������������������  553 Karin Rydenman, Stefan Berg, and Per Wekell 105 Recurrent Fever and Stomatitis������������������������������������������������������������  561 Ross Petty and Farhad Salehzadeh 106 Prolonged Fever and Swollen Joints����������������������������������������������������  565 Per Wekell, Stefan Berg, and Anders Fasth 107 Skeletal Pain in Knee and Clavicle������������������������������������������������������  575 Per Wekell, Anders Fasth, and Stefan Berg 108 Bone Pain in Upper Leg, Hip, Lower Back ����������������������������������������  583 Christian M. Hedrich 109 Enterocolitis Followed by Recurrent Sepsis-Like Episodes ��������������  591 Tania Siahanidou, Sofia Tantou, and Maria Kanariou 110 Recurrent Febrile Attacks, Myalgia and Livedo Reticularis ������������  597 Sezgin Sahin, Amra Adrovic, Kenan Barut, and Ozgur Kasapcopur 111 Sudden Dizziness, Somnolence and Diplopia��������������������������������������  603 Stefan Berg, Per Wekell, and Anders Fasth

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112 Recurrent Chest Pain����������������������������������������������������������������������������  611 Per Wekell, Anders Fasth, and Stefan Berg 113 Irregular Recurrent Fever��������������������������������������������������������������������  617 Per Wekell, Anders Fasth, and Stefan Berg 114 Fever, Headache and Photophobia ������������������������������������������������������  623 Crescent Darius Cossou-gbeto, Leila Dangou, Medeton Grâce Hounkpe, and Josephiel Fortunato 115 Recurrent Meningitis����������������������������������������������������������������������������  629 Ibtihal Benhsaien, Ahmed Aziz Bousfiha, and Fatima Ailal 116 Lupus, Macrophage Activation Syndrome, and Invasive Infections����������������������������������������������������������������������������������  633 Elizabeth Smith, Elizabeth Wisner, and Luke A. Wall 117 Recurrent Edema ����������������������������������������������������������������������������������  639 Peter Jandus 118 Recurrent, Non-Pitting Edema of Lips, Extremities, and Genitalia������������������������������������������������������������������������������������������  647 Taher Cheraghi 119 Recurrent Abdominal Pain ������������������������������������������������������������������  653 Michelle Korah-Sedgwick 120 Laryngeal Edema ����������������������������������������������������������������������������������  659 Alla Volokha 121 Lips Angioedema after Dental Procedure��������������������������������������������  663 Alireza Shafiei 122 Chronic Diarrhea, Recurrent Edema and Respiratory Infections ��������������������������������������������������������������������������  665 Ahmet Ozen, Elif Karakoc-Aydiner, and Deniz Ertem 123 Otitis Media and Gait Disturbance������������������������������������������������������  671 Javad Ghaffari 124 Regression of Her Ability to Walk��������������������������������������������������������  675 Alireza Shafiei 125 Microcephaly and a History of Recurrent Respiratory Infections ��������������������������������������������������������������������������  677 Anastasiia Bondarenko 126 Recurrent Respiratory Infections and Chronic Hepatic Disease������  683 Safa Baris and Ayca Kiykim

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127 Family Members with Congenital Heart Disease and Hypogammaglobulinemia ��������������������������������������������������������������������  689 Irina A. Tuzankina, Mikhail A. Bolkov, Svetlana S. Deryabina, and Elena V. Vlasova 128 Erythrodermic Rash and Seizures��������������������������������������������������������  695 Andrew R. Gennery 129 Bloody Diarrhea ������������������������������������������������������������������������������������  701 Rakesh Kumar Pilania, Rashmi Rekhi, and Deepti Suri 130 Leukocytoclastic Vasculitis��������������������������������������������������������������������  705 Rakesh Kumar Pilania, Rashmi Rekhi, and Deepti Suri 131 Progressive Renal Failure with Lymphopenia������������������������������������  707 Mollie Alpern and Roshini S. Abraham 132 Bloody Stool and Recurrent Infections������������������������������������������������  713 Sevgi Köstel Bal and Figen Doğu 133 Idiopathic Thrombocytopenic Purpura ����������������������������������������������  717 Maria Hatzistilianou, Marianna Janoudaki, Michel Massaad, Raif Geha, and Maria Kanariou 134 Allergy and Recalcitrant Wart��������������������������������������������������������������  721 Marzieh Tavakol 135 Recurrent Cutaneous and Sinopulmonary Infections������������������������  727 Angela Chang and Aisha Ahmed 136 Cold Abscesses and Lymphadenopathy ����������������������������������������������  733 María Claudia Ortega-López 137 Recurrent Pneumonia and Fracture in the Femur ����������������������������  737 Selma Scheffler-Mendoza, Juan Carlos Bustamante-Ogando, and Marco Yamazaki-Nakashimada 138 Fractures Following Minimal Trauma ������������������������������������������������  743 Julio C. Alcántara-Montiel, Aidé Tamara Staines-Boone, and Leopoldo Santos-Argumedo 139 Cough and Dyspnea ������������������������������������������������������������������������������  747 Javad Ghaffari 140 Skin Abscesses, Eczema and Lymphopenia ����������������������������������������  753 Elif Karakoc-Aydiner and Ahmet Ozen 141 Lymphopenia and Neutropenia������������������������������������������������������������  757 Alexandra Langlois and Reza Alizadehfar

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142 Red Peeling ��������������������������������������������������������������������������������������������  763 Ziying V. Lim and Emily Y. Gan 143 BCGosis and Hyperferritinemia����������������������������������������������������������  769 Neslihan Edeer Karaca, Guzide Aksu, and Necil Kutukculer 144 Mycobacterial Infection, Ectodermal Dysplasia and Thrombocytopenic Purpura������������������������������������������������������������������  777 Noé Ramírez-Alejo, Marco Yamazaki-Nakashimada, and Leopoldo Santos-Argumedo 145 Progressive Hypotonia with Lymphopenia������������������������������������������  781 Mihaela Tatiana Bataneant and Patricia Urtila 146 Painless Hematuria and Repaired Patent Ductus Arteriosus������������  787 Maria Hatzistilianou, Maria Stamou, Zoe Dorothea Pana, Ioannis Kyriakides, and Andreas Giannopoulos 147 Intractable Diarrhea and Failure to Thrive����������������������������������������  791 Beata Derfalvi 148 Alopecia, Hypothyroidism, Leukopenia and Hypogammaglobulinemia ��������������������������������������������������������������������  799 Maria Kanariou, Sofia Tantou, Marianna Tzanoudaki, and Lilia Lykopoulou Index������������������������������������������������������������������������������������������������������������������  805

Contributors

Roshini  S.  Abraham, PhD  Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, USA Amra  Adrovic  Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey Majid  Aflatoonian, MD  Department of Pediatrics Gastroenterology of Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran Aisha Ahmed, MD  University of California, San Francisco, San Francisco, CA, USA Fatima Ailal  Clinical Immunology Unit, Harouchi Children Hospital, Ibn Rochd Hospital University, Casablanca, Morocco Clinical Immunology, Autoimmunity and Autoinflammatory Laboratory (LICIA), Casablanca, Morocco Guzide Aksu, MD  Ege University Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey Julio  C.  Alcántara-Montiel, MD, PhD  Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV), National Polytechnic Institute (IPN), Mexico City, Mexico Reza Alizadehfar, MD  Division of Pediatric Allergy, Dermatology and Clinical Immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada Omar K. Alkhairy, MD, PhD  Department of Pathology and Laboratory Medicine, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia Abduarahman  Almutairi, MD  Department of Pediatrics, King Abdullah Specialist Children Hospital, Riyadh, Saudi Arabia

xxix

xxx

Contributors

Mollie Alpern, MD  Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA Salem H. Al-Tamemi, MD  Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman Stefano Amoroso, MD  University of Trieste, Trieste, Italy Wayne  Bainter, BSc, MMSc  Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Jalila  Bakkouri  Immunology Laboratory, Ibn Rochd Hospital University, Casablanca, Morocco Sevgi Köstel Bal, MD, PhD  Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey Safa Baris, MD  Marmara University Research and Training Hospital, Division of Pediatric Allergy and Immunology, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey Kenan Barut  Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey Mihaela Tatiana Bataneant, PhD  University of Medicine and Pharmacy “Victor Babes” Timisoara, Timisoara, Romania “Louis Turcanu” Children’s Emergency Clinical Hospital, Timisoara, Romania Nasrin  Behniafard, MD  Department of Allergy and Clinical Immunology of Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Ibtihal Benhsaien, MD  Clinical Immunology Unit, Harouchi Children Hospital, Ibn Rochd Hospital University, Casablanca, Morocco Clinical Immunology, Autoimmunity and Autoinflammatory Laboratory (LICIA), Casablanca, Morocco Moshe  Ben-Shoshan, MD  McGill University, Montreal General Hospital, Department of Allergy and Immunology, Montreal, QC, Canada McGill University, Montreal Children’s Hospital, Department of Pediatric Allergy and Immunology, Montreal, QC, Canada Stefan  Berg, MD, PhD  Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden Laura Berrón-Ruiz, MD  Unidad de Investigación Inmunodeficiencias Primarias, Instituto Nacional de Pediatría, Mexico City, Mexico

Contributors

xxxi

Mikhail A. Bolkov, PhD  Institute of Immunology and Physiology UB RAS, Ural Federal University, Yekaterinburg, Russia Andrey Bologov, MD, PhD  Russian Children’s Clinical Hospital, Moscow, Russia Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia Anastasiia  Bondarenko, MD, PhD  Shupyk National Medical Academy for Postgraduate Education, Department of Pediatric Infectious Diseases and Pediatric Immunology, Kiev, Ukraine Ahmed  Aziz  Bousfiha, MD  Clinical Immunology Unit, Harouchi Children Hospital, Ibn Rochd Hospital University, Casablanca, Morocco Clinical Immunology, Autoimmunity and Autoinflammatory Laboratory (LICIA), Casablanca, Morocco Lidia Branco, MD  Immunology Department, Centro Hospitalar do Porto, Porto, Portugal Juan  Carlos  Bustamante-Ogando, MD, MSc  Primary Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico Yildiz  Camcioglu, MD  Istanbul University, Cerrahpasa Medical School, Department of Pediatrics, Division of Infectious Diseases, Division of Clinical Immunology and Allergy, Cerrahpasa/Istanbul, Turkey Alice Y. Chan, MD, PhD  University of California San Francisco, Department of Pediatrics, Division of Allergy, Immunology and BMT, San Francisco, CA, USA Angela Chang, MD  Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, UCSF, San Francisco, CA, USA Pantipa Chatchatee, MD  Division of Allergy and Immunology, Immunology and Bone Marrow Transplant, UCSF, Bangkok, Thailand Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Bangkok, Thailand Zahra  Chavoshzadeh, MD  Department of Allergy and Clinical Immunology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Department of Allergy and Clinical Immunology, Pediatric Infectious Diseases Research Center, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Taher  Cheraghi, MD  Department of Pediatrics, 17th Shahrivar Children’s Hospital, Guilan University of Medical Sciences, Rasht, Iran Liudmyla  Chernyshova, MD, PhD  Shupyk National Medical Academy for Postgraduate Education, Department of Pediatric Infectious Diseases and Pediatric Immunology, Kiev, Ukraine

xxxii

Contributors

Suzan  Çınar, PhD  Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Fatih/Istanbul, Turkey Emilia  Cirillo, MD  Department of Translational Medical Sciences, Unit of Immunology, Federico II University of Naples, Naples, Italy Ester Conversano, MD  University of Trieste, Trieste, Italy Crescent Darius Cossou-gbeto, MD  Internal Medicine, Hematology and Oncology Department, Aix-en-Provence Hospital Center, Aix-en-Provence, France Chuvirov  Denis, MD  Advanced Study Institute of Federal Medico-Biologic Agency of Russia, Moscow, Russia Gunnur  Deniz, PhD  Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Fatih/Istanbul, Turkey Beata Derfalvi, MD, PhD  Department of Pediatrics, Dalhousie University/IWK Health Centre, Halifax, NS, Canada Svetlana S. Deryabina, PhD  Institute of Immunology and Physiology UB RAS, Ural Federal University, Yekaterinburg, Russia Romina  Dieli-Crimi, MD, PhD  Inmunóloga clínica, Facultativo Especialista Inmunología Servicio de Inmunología Hospital Universitario Vall d’Hebron, Edificio laboratorios clínicos, Barcelona, Spain Victoria  R.  Dimitriades, MD  Division of Pediatric Allergy, Immunology and Rheumatology, University of California Davis Health, Sacramento, CA, USA Figen Doğu, MD  Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey Joshua  M.  Dorn, MD  Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA Morna Dorsey, MD, MMSc  University of California San Francisco, Department of Pediatrics, Division of Allergy, Immunology and BMT, San Francisco, CA, USA Michael  E.  Dunham, MD  Pediatric Otolaryngology, Children’s Hospital and Louisiana State University School of Medicine, New Orleans, LA, USA Aziz  Eghbali, MD  Department of Pediatric Hematology & Oncology, Arak University of Medical Sciences, Arak, Iran Ülle Einberg, MD  Tallinn Childrens’ Hospital, Tallinn, Estonia Deniz  Ertem, MD  Division of Gastroenterology, Hepatology and Nutrition, Marmara University, Istanbul, Turkey Narges  Eslami, MD  Department of Allergy and Clinical Immunology, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Contributors

xxxiii

Theresa  Español, MD, PhD  Inmunóloga clínica, Facultativo Especialista Inmunología Servicio de Inmunología Hospital Universitario Vall d’Hebron, Edificio laboratorios clínicos, Barcelona, Spain Melissa Espinosa-Navarro  Clinical Immunology Department, Instituto Nacional de Pediatría, Mexico City, Mexico Sara Espinosa-Padilla, MD  Primary Immunodeficiency Diseases Research Unit, Instituto Nacional de Pediatría, Mexico City, Mexico Anders  Fasth, MD, PhD  Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden Josephiel  Fortunato, MD  Pediatric Department, Goho Hospital Center of Abomey, Abomey, Bénin Alexandra F. Freeman, MD  NIAID, Bethesda, MD, USA Vera  Gallo, MD  Department of Translational Medical Sciences, Unit of Immunology, Federico II University of Naples, Naples, Italy Emily  Y.  Gan, MBBS (Honours), MRCP (UK), MD  National Skin Centre, Singapore, Singapore Dermatology Service, KK Women’s and Children’s Hospital, Singapore, Singapore Raif  Geha, MD  Division of Allergy/Immunology/Rheumatology/Dermatology, Children’s Hospital, Harvard Medical School, Boston, MA, USA Metin  Yusuf  Gelmez, PhD  Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Immunology, Fatih/Istanbul, Turkey Geneviève Genest, MD  McGill University, Montreal General Hospital, Department of Allergy and Immunology, Montreal, QC, Canada Andrew R. Gennery, MD  Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Great North Children’s Hospital, Newcastle upon Tyne, UK Javad Ghaffari, MD  Mazandaran University of Medical Sciences, Sari, Iran Sergio Ghirardo, MD  University of Trieste, Trieste, Italy Andreas Giannopoulos, MD, PhD  2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Giuliana  Giardino, MD, PhD  Department of Translational Medical Sciences, Unit of Immunology, Federico II University of Naples, Naples, Italy Terry Harville, MD, PhD  Department of Pathology and Laboratory Services and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

xxxiv

Contributors

Sule Haskologlu  Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey Maria  Hatzistilianou, MD  2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Christian M. Hedrich, MD  Division of Paediatric Rheumatology and Immunology, Children’s Hospital Dresden, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany Department of Women’s & Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, UK Sarah  E.  Henrickson, MD, PhD  Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA Division of Allergy-Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Anna Hilfanova, MD, PhD  Shupyk National Medical Academy for Postgraduate Education, Department of Pediatric Infectious Diseases and Pediatric Immunology, Kiev, Ukraine Medeton  Grâce  Hounkpe, MD  ENT Department, University Hospital Hubert Koutoucou Maga of Cotonou, Cotonou, Benin Kamile Aydan Ikinciogulları  Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey Peter  Jandus, MD  Division of Immunology and Allergology, Department of Internal Medicine, University Hospital and Medical Faculty, Geneva, Switzerland Marianna Janoudaki, MD  Department of Immunology and Histocompatibility, “Aghia Sophia” Children’s Hospital, Athens, Greece Avni  Y.  Joshi, MD  Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA Maria  Kanariou, MD, PhD  Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies, Pediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece Hirokazu Kanegane, MD, PhD  Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan Neslihan Edeer Karaca, MD  Ege University Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey

Contributors

xxxv

Elif  Karakoc-Aydiner, MD  Division of Allergy and Immunology, Marmara University, Istanbul, Turkey Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey Manolya Kara, MD  Istanbul University, Istanbul Medical Faculty, Department of Pediatrics, Pediatric Infectious Diseases and Clinical Immunology, Fatih/İstanbul, Turkey Ozgur Kasapcopur  Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey Sandhya Kharbanda, MD  Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, UCSF, San Francisco, CA, USA Mojgan Kianiamin, MD  Chamran Medical Hospital, Tehran, Iran Ayca Kiykim, MD  Marmara University Research and Training Hospital, Division of Pediatric Allergy and Immunology, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey Irina  Kondratenko, MD, PhD  Department of Clinical Immunology and Rheumatology, Russian Children’s Clinical Hospital of Pirogov Russian National Research Medical University, Moscow, Russia Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia Michelle  Korah-Sedgwick, MD  Section of Pulmonary/Critical Care & Allergy/ Immunology, LSU Health New Orleans, New Orleans, LA, USA Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), New Orleans, LA, USA Kosmas Kotsonis, MD  1st Paediatric Clinic, “Aghia Sophia” Children’s Hospital, Athens, Greece Necil  Kutukculer, MD  Ege University Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey Ioannis Kyriakides, MD  2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Alexandra Langlois, MD  Division of Pediatric Allergy, Dermatology and Clinical Immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada Monica  G.  Lawrence, MD  Division of Asthma, Allergy and Immunology, University of Virginia, Charlottesville, VA, USA

xxxvi

Contributors

Juhee  Lee, MD  Division of Allergy & Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Kai  Lehmberg, MD, PhD  Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Centre Eppendorf, Hamburg, Germany Leila Dangou, MD  Pediatric Departement, Bethesda Hospital, Cotonou, Benin Ziying  V.  Lim, MBBS, MRCP (UK), MD  National Skin Centre, Singapore, Singapore Gabriela  López-Herrera, MD  Unidad de Investigación Inmunodeficiencias Primarias, Instituto Nacional de Pediatría, Mexico City, Mexico Lilia Lykopoulou, MD, PhD  First Department of Pediatrics, University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece Sarah Lena Maier, MD, MSc  Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Centre Eppendorf, Hamburg, Germany Mahboubeh  Mansouri, MD  Department of Immunology and Allergy, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Laura  Marques, MD  Paediatric Infectious Diseases and Immunodeficiencies Unit, Centro Materno-Infantil do Norte, Centro Hospitalar do Porto, Porto, Portugal Michel  Massaad, MD  Division of Allergy/Immunology/Rheumatology/ Dermatology, Children’s Hospital, Harvard Medical School, Boston, MA, USA Mehrnaz Mesdaghi, MD  Department of Allergy and Clinical Immunology, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran Reem Walid Mohammed, MD  Pediatric immunology and Allergy, Department of Pediatrics, King Faisal Specialist Hospital and research centre, Riyadh, Saudi Arabia College of Medicine, alfaisal University, Riyadh, Saudi Arabia Esmeralda  Neves, MD  Immunology Department, Centro Hospitalar do Porto, Porto, Portugal Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Porto, Portugal María  Claudia  Ortega-López, MD  Alejandra Ortega López Foundation, University Children’s Hospital of San José Bogotá-Colombia, Bogota, Cundinamarca, Colombia Dariia  Osypchuk, PhD  Institute of Pediatrics, Obstetrics and Gynecology, Laboratory of Immunology, Kiev, Ukraine

Contributors

xxxvii

Ahmet  Ozen, MD  Division of Allergy and Immunology, Marmara University, Istanbul, Turkey Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey Zoe  Dorothea  Pana, MD, PhD  2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Soumya  Pandey, MD  Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Nima Parvaneh, MD  Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran Olga  Pashchenko, MD, PhD  Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia Kiran  Patel, MD  Emory University, Department of Pediatrics, Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis, and Sleep, Atlanta, GA, USA Ross  Petty, MD, PhD  Pediatric Rheumatology, University of British Columbia, Vancouver, BC, Canada Ciriaco  A.  Piccirillo, MD  McGill University, Montreal General Hospital, Department of Allergy and Immunology, Montreal, QC, Canada Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, The Research Institute of the McGill University Health Center (RI-MUHC), Montreal, QC, Canada FOCiS Centre of Excellence in Translational Immunology (CETI), Montreal, QC, Canada Claudio Pignata, MD, PhD  Department of Translational Medical Sciences, Unit of Immunology, Federico II University of Naples, Naples, Italy Rakesh Kumar Pilania, MD  Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Nancy Jimenez Polvo, MD  Primary Immunodeficiency Diseases Research Unit, Instituto Nacional de Pediatría, Mexico City, Mexico Tamara  C.  Pozos, MD, PhD  Pediatric Infectious Diseases and Immunology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA Jennifer  Puck, MD  University of California, San Francisco, Department of Pediatrics, San Francisco, CA, USA

xxxviii

Contributors

Federica  Pulvirenti, MD, PhD  Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy Isabella  Quinti, MD, PhD  Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy Farzaneh  Rahmani, MD, MPH  Students Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran Noé Ramírez-Alejo, MD  St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA Rashmi  Rekhi, PhD  Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Nima  Rezaei, MD, PhD  Department of Immunology, School of Medicine, Research Center for Immunodeficiencies (RCID), Children’s Medical Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Daniel Rodriguez, MD  Department of Pediatrics, Section of Allergy Immunology, Children’s Hospital and Louisiana State University School of Medicine, New Orleans, LA, USA Karin Rydenman, MD, PhD  Department of Pediatrics, University of Gothenburg and NU-Hospital Group, Uddevalla, Sweden Sezgin Sahin  Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey Farhad  Salehzadeh, MD  Pediatric Rheumatology, Bouali Children’s Hospital, ARUMS Ardabil, Ardabil, Iran Lauren  A.  Sanchez, MD, MA  Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, UCSF, San Francisco, CA, USA Leopoldo Santos-Argumedo, MD  Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV), National Polytechnic Institute (IPN), Mexico City, Mexico Selma  Scheffler-Mendoza, MD  Immunology Department, National Institute of Pediatrics, Mexico City, Mexico Sara  Seghezzo, MD  University of California San Francisco, Department of Pediatrics, Division of Allergy, Immunology and BMT, San Francisco, CA, USA

Contributors

xxxix

Alireza Shafiei, MD  Department of Allergy and Clinical Immunology, Bahrami Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Samin Sharafian, MD  Department of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran Svetlana O. Sharapova, PhD  Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Research Department, Immunology Laboratory, Minsk Region, Belarus Kristin  Shimano, MD  Hematology/Oncology and Bone Marrow Transplant, Department of Pediatrics, UCSF Benioff Children’s Hospital, San Francisco, CA, USA Tania  Siahanidou, MD, PhD  First Department of Pediatrics, National & Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece Anna R. Smith, MD  Division of Asthma, Allergy and Immunology, University of Virginia, Charlottesville, VA, USA Elizabeth  Smith, MD  Louisiana State University School of Medicine, New Orleans, LA, USA Julia  K.  Sohn, MD  University of Virginia Health System, Charlottesville, VA, USA Aidé Tamara Staines-Boone, MD  Clinical Immunology Department, Hospital de Especialidades, Mexican Social Security Institute (IMSS), Monterrey, Nuevo Leon, Mexico Maria Stamou, MD, PhD  2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece Matthew Stark, MD  Department of Pathology, Children’s Hospital, New Orleans, LA, USA Yuriy Stepanovskiy, PhD  Shoupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine Kathleen  E.  Sullivan, MD, PhD  Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA Division of Allergy-Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Narissara Suratannon, MD  Division of Allergy and Immunology, Department of Pediatrics Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Bangkok, Thailand

xl

Contributors

Deepti Suri, MD  Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Samantha  Swain, MD  Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Health, Sacramento, CA, USA Andrea Taddio, MD  University of Trieste, Trieste, Italy Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy Sofia  Tantou, MD, PhD  Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies, Pediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece Markova  Tatyana, MD  Advanced Study Institute of Federal Medico-Biologic Agency of Russia, Moscow, Russia Marzieh  Tavakol, MD  Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran Department of Allergy and Clinical Immunology, Shahid Bahonar Hospital, Alborz University of Medical Sciences, Karaj, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Hamid Nawaz Tipu, MD, MBBS, FCPS  Immunology Department, Armed Forces Institute of Pathology, Rawalpindi, Pakistan Alberto Tommasini, MD  Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy Irina A. Tuzankina, MD  Institute of Immunology and Physiology UB RAS, Ural Federal University, Sverdlovsk Regional Children’s Hospital No. 1, Yekaterinburg, Russia Marianna Tzanoudaki, MD, PhD  Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies, Pediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece Patricia  Urtila, PhD  University of Medicine and Pharmacy “Victor Babes” Timisoara, Timisoara, Romania “Louis Turcanu” Children’s Emergency Clinical Hospital, Timisoara, Romania Svetlana  Vakhlyrskaya, MD, PhD  Clinical Immunology and Rheumatology Department, Russian Children’s Clinical Hospital of Pirogov Russian National Research Medical University, Moscow, Russia Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia

Contributors

xli

Julia  Vasconcelos, MD  Immunology Department, Centro Hospitalar do Porto, Porto, Portugal Sirje Velbri, MD, PhD  Tallinn Children’s Hospital, Tallinn, Estonia Edna  Venegas-Montoya, MD  Primary Immunodeficiency Diseases Research Unit, Instituto Nacional de Pediatría, Mexico City, Mexico Elena  V.  Vlasova, PhD  Sverdlovsk Regional Children’s Hospital No. 1, Yekaterinburg, Russia Alla  Volokha, MD, PhD  Shupyk National Medical Academy for Postgraduate Education, Department of Pediatric Infectious Diseases and Pediatric Immunology, Kiev, Ukraine Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Kiev, Ukraine Luke  A.  Wall, MD  Department of Pediatrics, Section of Allergy Immunology, Children’s Hospital and Louisiana State University School of Medicine, New Orleans, LA, USA Kathleen Y. Wang, MD  Department of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Per Wekell, MD, PhD  Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Elizabeth Wisner, MD  Section of Allergy/ Immunology, Children’s Hospital and Louisiana State University School of Medicine, New Orleans, LA, USA Marco  Yamazaki-Nakashimada, MD  Immunology Department, National Institute of Pediatrics, Mexico City, Mexico

Chapter 1

Introduction to Primary Immunodeficiencies Nima Rezaei, Soumya Pandey, Terry Harville, Anastasiia Bondarenko, Farzaneh Rahmani, Svetlana O. Sharapova, Per Wekell, Crescent Cossou-Gbeto, and Sevgi Köstel Bal

When a clinician suspects an underlying immunodeficiency disorder, it is crucial to note and rule out a variety of secondary causes of immunodeficiency that are cumulatively more frequent than PIDs. This becomes even more important when assessing adolescents and adults with recurrent, aggressive, and/or unusual infections. The International Union of Immunological Societies (IUIS) has recently updated the classification of primary immunodeficiencies, as shown in Table  1.1 [1, 2], ­comprising more than 350 different types of PIDs. This growing list is still counting and with whole genome exome sequencing of patients and families with N. Rezaei (*) Department of Immunology, School of Medicine, Research Center for Immunodeficiencies (RCID), Children’s Medical Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran e-mail: [email protected] S. Pandey Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA T. Harville Department of Pathology and Laboratory Services and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA A. Bondarenko Shupyk National Medical Academy for Postgraduate Education, Department of Pediatric Infectious Diseases and Pediatric Immunology, Kiev, Ukraine F. Rahmani Students Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran

© Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_1

1

2

N. Rezaei et al.

S. O. Sharapova Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Research Department, Immunology Laboratory, Minsk Region, Belarus P. Wekell Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg and NU-Hospital Group, Uddevalla, Sweden C. Cossou-Gbeto Internal Medicine, Hematology and Oncology Department, Aix-en-Provence Hospital Center, Aix-en-Provence, France S. K. Bal Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey

immunodeficiencies being  increasingly available, continues to grow.  A detailed explanation of the PIDs can be found Second Edition of the text-book, Primary Immunodeficiency Diseases: Definition, Diagnosis and Management, by Rezaei et al. (Springer 2017). In born defects in the humoral immunity, i.e. antibody deficiencies, are introduced as a prototype group of PIDs, with the hallmark clinical presentation of recurrent sinopulmonary infections [3]. Measurement of serum antibody levels is the primary screening test to diagnose antibody deficiencies, while  measurement of pre−/post-immunization specific antibody values is the most accurate method of establishing a defect in production of antibodies. Most commonly, these specific antibodies will be against the diphtheria and tetanus toxoid vaccines and the 23-valent pneumococcal polysaccharide vaccine (PPV or PPV23) [1, 3]. Curiously, many of the primary antibody deficiencies are now recognized to be associated with autoimmune conditions. In this context, obtaining a family history might be confusing, when no history of immunodeficiency can be tracked, but several members present with autoimmune conditions. Common PIDs presenting with the hallmark of humoral immunodeficiency will be discussed in Chaps. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 of this book. Table 1.2 summarizes gene defects and laboratory findings associated with this group of PIDs.  Table 1.1  Main groups of primary immunodeficiencies

I. Immunodeficiencies affecting cellular and humoral immunity II. Combined Immunodeficiences with associated or syndromic features III. Predominantly Antibody deficiencies IV. Diseases of immune dysregulation V. Congenital defects of phagocyte number, function, or both VI. Defects in Intrinsic and Innate immunity VII. Auto-inflammatory disorders VIII. Complement deficiencies IX. Phenocopies of PID

BLNK (AR) CD19 (AR) CD20 (AR)

CD21 (AR) TNFRSF7 (AR)

TNFRSF5 (AR)

CD81 (AR) DNMT3B, ZBTB24 (AR) Polygenic

CTLA4 (AR)

BLNK deficiency CD19 deficiency CD20 deficiency

CD21 deficiency CD27 deficiency

CD40 deficiency (AR-HIGM)

CD81 deficiency Centromeric Instability ICF

CTLA4 (GoF)

Common Variable Immune Deficiency (CVID)

TNFRSF13C (AR) BCL10 (AR)

Immunodeficiency AID Deficiency (AR-hyper IgM disease (HIGM) BAFF receptor deficiency BCL10 deficiency

Gene(s) (Inheritance Pattern) AID (AR)

IgM increased or normal, low IgG and IgA/ Poor Low IgG, low or normal IgA and IgM/Poor Normal or low IgG, variably normal to low IgA, IgM/Poor IgG must be low, with low IgA or low IgM or both low (IgM may increase while IgA and IgG decrease)/Poor Low IgG, variably normal to low IgA and IgM/ Poor

Very low/Absent Low IgG, IgA, with normal or low IgM/Poor Low IgG, normal or elevated IgM and IgA/ Poor Low IgG/Poor anti-pneumococcal Low, IgG, IgA, IgM after Epstein-Barr virus infection/Poor

Immunoglobulin Levels/Specific Antibody Serum Levels Normal or high IgM with low IgG and IgA/ Absent Low IgG and IgM/Poor Low/Poor

(continued)

Low B Lymphocytes/Low Switched-Memory B Lymphocytes/Low Memory T Lymphocytes/ Lymphoproliferation/Autoimmunity

Variable T and B Lymphocyte Subpopulations/ Various Autoimmunities

Absent CD21 Expression Low levels of iNKT Lymphocytes/Disease Triggered by Epstein-Barr virus/Hemophagocytic Lymphohistiocytosis/Aplastic Anemia/Lymphoma Absent Switched-Memory B Lymphocytes/ Neutropenia/GI Disease Absent CD81 Expression/Glomerulonephritis Dysmorphic Features

Additional Information Absent Switched-Memory B Lymphocytes/ Lymphoproliferation Variable Disease Expression Low Memory Subsets of T and B Lymphocytes/ GI Disease/Recurrent Viral Infections/Candidiasis Absent B Lymphocytes Absent CD19 Expression/Glomerulonephritis Absent CD20 Expression

Table 1.2  Gene mutations, inheritance patterns, immunoglobulin levels, specific antibody serum levels, and additional information for antibody deficiencies

1  Introduction to Primary Immunodeficiencies 3

DOCK8 (AR)

PGM3 (AR)

ICOS (AR)

Polygenic

Unknown

CD79A (AR) CD79B (AR) IL-21 (AR)

IL-21R (AR)

INO80 (AR)

Hyper IgE Syndrome (HIES) (AR)

ICOS deficiency

IgA Deficiency (IGAD)

IgG Subclass Deficiency

Igα deficiency Igβ deficiency IL-21 deficiency

IL-21R deficiency

INO80

Increased IgE, with normal to occasionally slightly low IgG, IgA, IgM/Variably Poor

STAT3 (AD)

Additional Information Absent B Lymphocytes

Decreased Non-Class-Switched and Class-­ Switched Memory B lymphocytes/Candida Infections of Skin and Nails/Cold Abscesses/ Staph Pneumatoceles Increased IgE, with normal IgG, IgA and low Decreased Memory B and T lymphocytes/ IgM/Poor Neutropenia/Candida Infections of Skin and Nails/ Cold Abscesses/Staph Pneumatoceles Increased IgE, with typically normal to Candida Infections of Skin and Nails/Cold increased IgG, IgA and normal IgM/Normal Abscesses/Staph Pneumatoceles/Bronchiectasis/ Vasculitis/Autoimmunity/Neuro-cognitive Dysfunction Low IgG, IgA, IgM/Poor Low Switched-Memory B Lymphocytes/GI Disease/Granuloma Formation/Autoimmunity Normal IgG, IgM with IgA less than Detectable No Clinical Disease in Most/If Clinical Limits of the assay/Normal Manifestations, Re-Evaluate for CVID Normal to low Total IgG with one or more low Possibly No Clinical Manifestations — IgG1, 2, 3, 4/Normal to Poor Re-Evaluate for CVID is Clinical Disease is Present Very low/Absent Absent B Lymphocytes Very low/Absent Absent B Lymphocytes Low IgG/Poor Low B Lymphocytes/Low Switched-Memory B Lymphocytes/Colitis Normal/Poor Low B Lymphocytes/Low Switched-Memory B Lymphocytes/Cholangitis Low IgG, IgA with IgM increased/Poor Low Switched-Memory B Lymphocytes/Radiation Sensitivity

Immunoglobulin Levels/Specific Antibody Serum Levels Very low/Absent

Gene(s) (Inheritance Pattern) TCF3 (AR)

Hyper IgE Syndrome (HIES) (AR)

Immunodeficiency E47 transcription factor deficiency Hyper IgE Syndrome (HIES) (AD)

Table 1.2 (continued)

4 N. Rezaei et al.

Normal/Poor anti-pneumococcal

Normal to Decreased B lymphocytes/Typically For CVID, IgG must be low, with low IgA or low IgM or both low (IgM may increase while increased CD8 T Lymphocytes/T Lymphocytes IgA and IgG decrease)/Poor; For IGAD2 (early Over-express CD45RO/Autoimmunity CVID?), low IgA with normal IgG, IgM/ normal to somewhat poor anti-pneumococcal

IGHM (AR) NFKB2 (AR)

MAP3K14 (AR)

PIK3R1 (AR) PIK3CD (AD)

PI3KR1 (AD)

Unknown

TNFRSF13B (AR, AD)

μ heavy chain deficiency NFKB2 deficiency

NIK deficiency

PI3 kinase deficiency (LOF) PI3K-Cδ (GOF)

PI3KR1 (LOF)

Specific Antibody Deficiency (SAD) TACI mutation (CVID, IGAD2)

Absent IgA, low IgG/Poor

Very low/Absent Normal to low total IgG, IgA, with decreased IgG2 and normal to increased IgM/Poor anti-pneumococcal

Low IgG, IgA, IgM/Poor

Normal to low IgG with normal to increased IgM/Poor Very low/Absent Low IgG, IgA, IgM/Poor

MSH6 (AR)

(continued)

Absent B Lymphocytes Normal to Low B Lymphocytes/Adrenal Insufficiency Low NK cell counts/Decreased NK cell function/ Cryptosporidium GI Infections Absent B Lymphocytes Low Switched-Memory B Lymphocytes/ Decreased T lymphocytes/Bronchiectasis begins early/Chronic EBV or cytomegalovirus Infections/ Autoimmunity Chronic Epstein-Barr virus or cytomegalovirus Infections/Poor Growth Lymphocyte Enumeration may be Normal

Low Switched-Memory B Lymphocytes/Cancer

Very low/Near-normal

MOGS (AR)

Absent B Lymphocytes Low Switched-Memory B Lymphocytes/Low Memory T Lymphocytes/Lymphoproliferation/ Inflammatory Bowel Disease/Autoimmunity/ Recurrent EBV Infections Neurologic Autoimmunity

Mannosyl-oligosaccharide glucosidase deficiency MSH6

Very low/Absent Typically low IgG and IgA/Poor

IGL1 (AR) LRBA (AR)

λ 5 deficiency LRBA deficiency

1  Introduction to Primary Immunodeficiencies 5

Low IgG/Poor

Very low/Absent Normal to increased IgM with low IgG, IgA/ Absent

TRNT1 (AR)

TTC37 (AR)

TNFSF12 (AR) UNG (AR)

BTK (XL)

CD40L (XL)

TTC37 deficiency

TWEAK deficiency UNG deficiency (AR-HIGM)

X-linked Agammaglobulinemia (XLA) X-linked Hyper IgM (XHIGM)

Normal B Lymphocyte count/Absent Switched-­ Memory B Lymphocytes/Low CD4 Memory T Lymphocytes/Neutropenia/Pneumocystis Pneumonia/Autoimmunity/GI disease/Cancer risks

Low B Lymphocytes/Development of Deafness/ Developmental Delay/Anemia Inflammatory Bowel Disease/Trichorrhexis Nodosa Warts/Thrombocytopenia/Neutropenia Absent Switched-Memory B Lymphocytes/ Lymphadenopathy Absent B Lymphocytes/Occasional Neutropenia

Additional Information Lymphocyte Enumeration may be Near-Normal to Normal

a

This table is a partial listing of the known mutations, which result in antibody deficiencies, noting the more common and well-documented ones. The first column provides the name for the immunodeficiency. The second column provides information about the gene mutation and inheritance pattern. The third column provides information about the typical serum immunoglobulin levels and specific antibody levels. The fourth column provides additional information, including, the most typical immunophenotype patterns, infection patterns, types of autoimmunities, and additional features, such as organs affected and cancer risks b AD autosomal dominant, AR autosomal recessive, GOF gain-of-function, LOF loss-of-function

Low IgM, IgA/Poor anti-pneumococcal Low IgG, IgA with increased IgM/Poor

Frequently normal/Poor anti-pneumococcal

Immunoglobulin Levels/Specific Antibody Serum Levels Low IgG, normal to low IgA, IgM/Typically near-normal antibody responses

Gene(s) (Inheritance Pattern) Unknown

Immunodeficiency Transient Hypogammaglobulinemia of Infancy (THI) TRNT1 deficiency

Table 1.2 (continued)

6 N. Rezaei et al.

1  Introduction to Primary Immunodeficiencies

7

Combined immunodeficiencies are among the most severe and life-threatening groups of congenital disorders of the immune system. Lymphopenia in complete blood count, absence of the thymus, family history of early childhood death, and unusual, severe infections, should raise suspicion for combined immunodeficiency disorders (CID). CIDs are identified with the “severe combined immunodeficiencies (SCID)” a common phenotype yielding to a generally profound cellular and humoral immunity defect, associated with predominant T-lymphocyte dysfunction. SCID is clinically defined based on T cell lymphopenia (CD3+ T cells 2 weeks). TRAPS is an autosomal dominant disease, but the fever episodes are usually more than 1–2 weeks, longer than 1–5 days in the present case and the disease onset is usually later in life. There is an overlap between duration of fever episodes in our patient with FMF (0.8 μkat/L)    Triglycerides >156 mg/dL (1.76 mmol/L)   Fibrinogen ≤3.6 g/L

of MAS. This is contrasted by high ESR and CRP seen in bacterial infections and SoJIA. It has been suggested that the strongest discriminatory variable to differentiate MAS from sepsis is ferritin level [18]. Although MAS is the most likely diagnosis in this case, antibiotic treatment is recommended until cultures come back negative. The relation between infections and MAS is complex, as MAS on one hand can be complicated by opportunistic infections, and on the other triggered by bacterial and viral infections, especially by EBV [19]. This is important to bear in mind when to decide upon antibiotic and antiviral treatment. MAS is a pediatric emergency and might need intensive care with respiratory and/or circulatory support and close collaboration between different specialties. Q5. Which of the following laboratory finding is not compatible with MAS in the context of SoJIA? A. Anemia B. Neutropenia C. Increase in fibrinogen D. Increase in lactate dehydrogenase Answer:  The correct answer is C. High fibrinogen is against a diagnosis of MAS. Low serum fibrinogen also provides bases to understand decreased ESR seen in MAS. Anemia, neutropenia and increased lactate dehydrogenase are in keeping with MAS. Q6. What is the first treatment option in management of a patient with MAS associated with SoJIA? A. Cyclosporine A B. High-dose intravenous methylprednisolone C. Intravenous immunoglobulins D. IL-1 blocking agents Answer:  The correct answer is B. There are no evidence-based treatment guidelines for MAS in SoJIA and early expert advice should be sought when MAS is suspected. A detailed discussion on the treatment of MAS in SoJIA is beyond the scope of this case study. High-dose intravenous methylprednisolone is recommended as a first-line treatment by most experts. In children without a rapid respond to corticosteroids and deterioration of symptoms, cyclosporine A, etoposide and intravenous immunoglobulin are commonly

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used. Several case reports have found different cytokine blocking agents to be effective in MAS, in particular IL-1 and IL- 6 blockade. These should not be used as first line drugs, but may be considered as alternative second or third line drug. One problem with specific cytokine blockade is that it is not clear which cytokine/s drive the disease in the individual patient. In addition to IL-1 and IL-6, IL-18 and INFγ are important cytokines at play in MAS associated to SoJIA [20]. As mentioned earlier, adequate antibiotic treatment is important when sepsis cannot be ruled out, when SoJIA is complicated by opportunistic infection, or when a bacterial trigger needs to be targeted. If EBV is identified as a possible trigger, depletion of B lymphocytes, a primary repertoire for viral replication, using the monoclonal antibody rituximab should be considered.

Practical Points • The diagnosis of systemic onset juvenile idiopathic arthritis (SoJIA) is based on clinical features including: prolonged quotidian fever, erythematous rash during fever spikes, generalized lymph node enlargement, arthralgia/arthritis and splenomegaly • Glucocorticoids are the first-line treatment of SoJIA • Approximately 10% of patients with SoJIA develop macrophage activation syndrome (MAS) associated with significant mortality • The main complication of SoJIA is MAS characterised by: 1. Clinical features such as continuous fever, petechial rash, hepatosplenomegaly and compromised circulation, 2. laboratory findings such as cytopenias in two or more cell lines, increased ferritin, liver transaminases, lactate dehydrogenase and triglycerides • There are no evidence-based treatment guidelines for MAS in SoJIA. Early expert advice should be sought. High-dose intravenous methylprednisolone is recommended as a first-line treatment

References 1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-­ Cocco J, Orozco-Alcala J, Prieur AM, Suarez-Almazor ME, Woo P. International league of associations for R. international league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–2. 2. Gurion R, Lehman TJ, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam. 2012;2012:271569. 3. Kastner DL, Aksentijevich I, Goldbach-Mansky R.  Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784–90. 4. Sandborg C, Mellins ED. A new era in the treatment of systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2439–40. 5. Martini A. Systemic juvenile idiopathic arthritis. Autoimmun Rev. 2012;12(1):56–9.

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6. Lovell DJ, Giannini EH, Reiff AO, Kimura Y, Li S, Hashkes PJ, Wallace CA, Onel KB, Foell D, Wu R, Biedermann S, Hamilton JD, Radin AR. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2013;65(9):2486–96. 7. Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, Bossuyt X, Boutten A, Bienvenu J, Duquesne A, Richer O, Chaussabel D, Mogenet A, Banchereau J, Treluyer JM, Landais P, Pascual V. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70(5):747–54. 8. Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, Brik R, McCann L, Kasapcopur O, Rutkowska-Sak L, Schneider R, Berkun Y, Calvo I, Erguven M, Goffin L, Hofer M, Kallinich T, Oliveira SK, Uziel Y, Viola S, Nistala K, Wouters C, Cimaz R, Ferrandiz MA, Flato B, Gamir ML, Kone-Paut I, Grom A, Magnusson B, Ozen S, Sztajnbok F, Lheritier K, Abrams K, Kim D, Martini A, Lovell DJ, Printo P. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2396–406. 9. Vastert SJ, de Jager W, Noordman BJ, Holzinger D, Kuis W, Prakken BJ, Wulffraat NM. Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthrit Rheumatol (Hoboken, NJ). 2014;66(4):1034–43. 10. De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, Cuttica R, Ravelli A, Schneider R, Woo P, Wouters C, Xavier R, Zemel L, Baildam E, Burgos-Vargas R, Dolezalova P, Garay SM, Merino R, Joos R, Grom A, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A, Printo P. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95. 11. Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, Laxer RM, Lovell DJ, Nigrovic PA, Robinson AB, Vehe RK. American Collge of R. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile ­idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499–512. 12. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006;2(1):28–34. 13. Hafner R, Truckenbrodt H. Course and prognosis of systemic juvenile chronic arthritis--retrospective study of 187 patients. Klin Padiatr. 1986;198(5):401–7. 14. Spiegel LR, Schneider R, Lang BA, Birdi N, Silverman ED, Laxer RM, Stephens D, Feldman BM. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum. 2000;43(11):2402–9. 15. Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, Arico M, Avcin T, Behrens EM, De Benedetti F, Filipovic L, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ, Paediatric Rheumatology International Trials O, Childhood A, Rheumatology Research A, Pediatric Rheumatology Collaborative Study G, Histiocyte S. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016;75(3):481–9. 16. Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, Lehmberg K, Weitzman S, Insalaco A, Wouters C, Shenoi S, Espada G, Ozen S, Anton J, Khubchandani R, Russo R, Pal P, Kasapcopur O, Miettunen P, Maritsi D, Merino R, Shakoory B, Alessio M, Chasnyk V, Sanner H, Gao YJ, Huasong Z, Kitoh T, Avcin T, Fischbach M, Frosch M, Grom A, Huber A, Jelusic M, Sawhney S, Uziel Y, Ruperto N, Martini A, Cron RQ, Ravelli A, Pediatric Rheumatology International Trials O, Childhood A, Rheumatology Research A, Pediatric Rheumatology Collaborative Study G, Histiocyte S. Clinical features, treatment, and outcome of macrophage

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activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66(11):3160–9. 17. Ramanan AV, Schneider R. Macrophage activation syndrome—what’s in a name! J Rheumatol. 2003;30(12):2513–6. 18. Davi S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, Bovis F, Cimaz R, Gamir ML, Ilowite NT, Kone-Paut I, Feitosa de Oliveira SK, McCurdy D, Silva CA, Sztajnbok F, Tsitsami E, Unsal E, Weiss JE, Wulffraat N, Abinun M, Aggarwal A, Apaz MT, Astigarraga I, Corona F, Cuttica R, D’Angelo G, Eisenstein EM, Hashad S, Lepore L, Mulaosmanovic V, Nielsen S, Prahalad S, Rigante D, Stanevicha V, Sterba G, Susic G, Takei S, Trauzeddel R, Zletni M, Ruperto N, Martini A, Cron RQ, Ravelli A, Paediatric Rheumatology International Trials Organisation tCA, Rheumatology Research Alliance tPRCSG, the Histiocyte S. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthrit Rheumatol (Hoboken, NJ). 2014;66(10):2871–80. 19. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12(5):259–68. 20. Shimizu M, Yokoyama T, Yamada K, Kaneda H, Wada H, Wada T, Toma T, Ohta K, Kasahara Y, Yachie A. Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-­associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis. Rheumatology (Oxford). 2010;49(9):1645–53.

Chapter 107

Skeletal Pain in Knee and Clavicle Per Wekell, Anders Fasth, and Stefan Berg

A 12-years-old presents with a history of pain in her right knee for 6 months, and a four-month history of pain in her right clavicle. On examination, her right knee is slightly warm with normal mobility and is not swollen. The right clavicle has a bony swelling on palpation. There is no history of fever, skin disease, red eyes, or gastrointestinal problems. She is otherwise healthy without any significant medical history. Among her first-degree relatives there is no similar history or history of rheumatic diseases, malignancy or immunodeficiency. Basic laboratory variables show CRP 1.3 mg/dL, ESR 19 mm/h, WBC: 9700 /μL, platelets: 352,000 /μL and hemoglobin: 11.8 g/dL. Differential count shows neutrophils: 5600 /μL and lymphocytes: 3000 /μL. Radiograph of the patient’s knee and a photo of her clavicles is shown in Fig. 107.1a and b respectively. X-ray of the clavicle is not shown but the report stated that there was a lesion in the medial half of the clavicle with a periosteal reaction. Q1. What is the most probable diagnosis? A. Lymphoma B. Chronic non-bacterial osteomyelitis C. Leukemia

P. Wekell (*) Department of Pediatrics, NU-Hospital Group, Uddevalla, Sweden Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden A. Fasth · S. Berg Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_107

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Fig. 107.1  Radiograph of the knee (a), and bilateral clavicles (b), of a teenage girl with chronic bone pain

D. Bacterial osteomyelitis Answer:  The correct answer is B. According to the limited clinical information in this case, chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is the most probable diagnosis due to typical location of the lesion in the clavicle. CNO/ CRMO belongs to the autoinflammatory bone disorders that are characterized by dysregulation of innate immunity causing inflammation in typically sterile bone [1–3]. It is important to note that CNO/CRMO is a diagnosis of exclusion i.e. infections and malignancies need to be excluded [3, 4]. Primary multifocal intraosseous lymphoma may mimic CRMO and may appear as a bone lesion without involvement of lymph nodes or other organs [3, 5]. The location of the lesion in the clavicle makes intraosseous lymphoma unlikely. The same holds true for leukemia that is unlikely, due to the location in the clavicle together with normal blood count and differential. Bacterial osteomyelitis is unlikely owing to the long history of lesions, location of the lesion in the clavicle and limited increase in inflammatory markers including CRP and ESR. Most cases of autoinflammatory bone disorders are sporadic, but there are a few monogenic conditions described. These include deficiency of interleukin-1 receptor antagonist (DIRA), with mutation in IL1RN gene, Majeed syndrome (mutation in LPIN2 gene) and cherubism (mutation in gene SH3BP2) [6–9]. Q2. After performing plain X-ray, which of the following investigation is the next best step in evaluation of this patient? A. Needle biopsy B. Bone scintigraphy C. Magnetic resonance imaging of the symptomatic lesions D. Computer tomography scan of the symptomatic lesions Answer:  The correct answer is C.

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The next step in the investigation of this patient should be to refer the patient for an MRI of the symptomatic lesion/s. Note, that a plain X-ray may be normal early in the disease course. MRI findings that support CNO are: bone marrow edema, adjoining soft tissue inflammation, transphyseal disease and/or periosteal reaction [10], but no MRI finding is pathognomonic for CNO.  MRI of the symptomatic lesions can be combined or supplemented with whole-body MRI if available. The latter is the best method to visualize multiple lesions including silent ones [11]. If whole body MRI is not available, multiple lesions can be depicted by bone scintigraphy [4]. A decision to perform a biopsy is made on the bases of the clinical features and MRI findings together with the location and number of lesions. A biopsy may be postponed when; the lesion/s is/are located at very characteristic site/s, or when there is comorbid psoriasis or inflammatory bowel disease, as patients with the latter two conditions are predisposed to develop CNO. Biopsy is recommended for single lesions with a location other than clavicle. Other features that support the decision to perform a biopsy are: presence of fever, highly elevated inflammatory markers (CRP, ESR), blood count or differential indicating leukemia, other malignancies or bacterial infection, and elevated levels of uric acid or LDH [12]. The biopsy should, besides pathological examination, be sent for culture and PCR for bacteria including mycobacteria and fungi. CT scan imaging is less specific for evaluation of CNO and exposes the patient to substantial irradiation. If Langerhans cell histiocytosis is suspected, the biopsy material should be stained with hematoxylin and eosin as well as for CD1a and/or CD207 (langerin), the latter is required for definitive diagnosis [13]. The radiology department managed to carry out an MRI of the clavicle and right knee the same day. The report states that the lesions are compatible with osteomyelitis with bone edema, adjoining soft tissue inflammation and periosteal reaction. Although the radiological report stated no clear signs of malignancy, the radiologist adds that cortical disruption cannot be ruled out in the lesion in the knee. Hence, a biopsy is planned within 2 days. Q3. Which of the following treatment options may interfere with the results of the workup for malignancy? A. Treatment with antibiotics B. Defer treatment until the etiology is better known C. Treatment with Cox-inhibitors (NSAIDs) D. Treatment with corticosteroids Answer:  The correct answer is D. If malignancy needs to be ruled out - biopsy and histopathological examination of the biopsy material is the way forward. In such cases, initiation of the treatment with corticosteroids should be deferred until the result of the biopsy is available [14]. If steroid treatment is given before the biopsy, it may; muddle the histopathological workup, defer appropriate treatment and worsen the prognosis of a malignancy [14]. Cox-inhibitors can be started before the biopsy without complicating the investigation. Treatment with antibiotics will not compromise the workup of a

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possible malignancy. In this case, bacterial osteomyelitis is unlikely, and taken into account the long history, the decision to start antibiotics can be postponed until the results of the cultures, PCR and pathological examination is known. In summary, CNO is a diagnosis of exclusion and a bone biopsy is often needed to confirm the diagnosis and fully exclude bacterial osteomyelitis and malignancy [1, 3, 10]. Q4. A biopsy of the lesion in the right knee was performed and the report from the pathologist shows normal bone tissue. How would you interpret the diagnosis? A. The biopsy exclude malignancy B. The biopsy is compatible with CNO C. The normal biopsy indicate that the biopsy may have been taken from the wrong locality D. The biopsy excludes bacterial osteomyelitis Answer:  The correct answer is C. A normal biopsy indicates that the biopsy was taken from the wrong locality and no conclusion of the nature of the lesion can be drawn from the examination. That is, the biopsy does not support CNO, neither does it exclude malignancy or bacterial osteomyelitis. A second biopsy is performed, in this case guided by a CT scan. The analyses of the biopsy material yielded the following results: bacterial cultures and PCR are negative, PCR for tuberculosis is negative and culture for tuberculosis is pending, fungal culture and PCR are negative. The pathological examination of the biopsy material showed infiltration of lymphocytes, plasma cells, histiocytes and increased osteoblast activity in keeping with the rather long history of this patient’s symptoms [4, 10, 12]. There were no malignant cells or findings that supported tuberculosis at the pathological examination. Q5. What is the treatment of choice in this patient? A. IL-1 blockade B. Bisphosphonates C. Cox-inhibitors (NSAIDs) D. Corticosteroids E. TNF blockade Answer:  The correct answer is C. It is important to note that there is no randomized placebo controlled trials of the treatment of CNO [10]. Recommended first-line treatment in uncomplicated cases of CNO is Cox-inhibitors (NSAIDs) with an estimated symptomatic relief in approximately half of the patients [12, 15]. Cox-inhibitors seem to be more efficient in patients with limited disease [12]. The proportion of children with complete remission is lower if complete remission is defined as absence of pain, normalization of CRP and ESR together with absence of defined inflammatory changes on MRI [16, 17]. These results indicate that the outcome of the treatment should be evaluated by multiple modalities, including relief of pain and swelling,

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inflammatory variables such as CRP, ESR and SAA as well as disease activity on MRI or whole-body MRI [4, 16]. In this patient a bone scintigraphy was undertaken, instead of a whole-body MRI. The report from the bone scintigraphy stated that there are additional lesions in the body at T4, T7 and T8 vertebrae. MRI of the spine and thorax shows that the lesions depicted by the bone scintigraphy are compatible with osteomyelitis, and that there is a compression fractures in T8. Q6. What is the most appropriate interpretation of the clinical situation? A. These findings support the diagnosis of CNO/CRMO and will not affect the planned trail of treatment with Cox-inhibitors (NSAIDs) for 3 months B. The findings of silent lesions at these sights will make the diagnosis of CNO/ CRMO unlikely and the diagnosis will be reevaluated C. These findings are compatible with the diagnosis of CNO/CRMO, but the involvement of the spine with structural damage indicates that a more aggressive treatment regime is warranted D. These findings support the diagnosis of CNO/CRMO and will increase the length of the planned trail with cox-inhibitors (NSAIDs). Answer:  The correct answer is C. Patients that present with structural damage in the spine including vertebral fractures should be treated more aggressively [2, 12]. Treatment of CNO is empirical and preferences vary between different centers and experts, and alternatives include glucocorticoids, anti-TNF agents and bisphosphonates [1, 2, 15]. In our center, we prefer to use bisphosphonates in case of vertebral involvement, however, no randomized trials have been conducted to clarify, which treatment is most efficacious. Q7. CNO is often associated with extra-skeletal involvement. Which of the following alternatives represent the three most likely organs involved other than the axial skeleton? A. Liver, skin and gastrointestinal tract B. Joints, liver and gastrointestinal tract C. Gastrointestinal tract, joints and skin D. Gastrointestinal tract, lungs and skin Answer:  The correct answer is C. Involvement of the gastrointestinal tract, joints and skin are common in CNO [4]. In gastrointestinal tract Crohn’s disease is of particular importance. Skin manifestations include severe acne, palmoplantar pustulosis and psoriasis. Onset of skin lesions can occur simultaneously, before or after the onset of bone involvement. Q8. Which of the following statements best describe the prognosis of this patient? 1. As in most cases CNO this patient will most probably have a self-limiting disease without long-term sequel or morbidity 2. There is a substantial risk that this patient will have an active disease and permanent bone deformity in the long-term perspective.

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3. The patient will have a worse prognosis than children with an onset before the age of 2 years. 4. There is a risk that the patient may develop atypical spondyloarthropathy A. B. C. D.

1, 2 2, 4 3, 4 1, 4

Answer:  The correct answer is B. The prognosis in CNO is variable, however there is a substantial risk that this patient will develop permanent bone deformity and long-term morbidity. In particular the spinal involvement may lead to vertebral compression fractures, vertebra plana, or vertebral hemifusion [2, 12, 18]. Patients with CNO are also at increased risk to develop atypical spondyloarthropathy [2, 12, 19]. The belief that CNO is a self-limiting disease without sequel or co-morbidity, is probably based on short-­ term follow-up [14]. Practical Points • CNO/CRMO is characterized by sterile bone inflammation commonly located in the metaphysis of long bones, the clavicle, spine, and the pelvis • Bone lesions can be both symptomatic and asymptomatic • CNO/CRMO is a diagnosis of exclusion and a bone biopsy is often needed to confirm the diagnosis and exclude other disorders • Empirical treatment options include; Cox-inhibitors (NSAIDs), glucocorticoids, anti-TNF agents and bisphosphonates

References 1. Morbach H, Hedrich CM, Beer M, Girschick HJ.  Autoinflammatory bone disorders. Clin Immunol (Orlando, Fla). 2013;147(3):185–96. 2. Ferguson PJ, Sandu M. Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep. 2012;14(2):130–41. 3. Stern SM, Ferguson PJ.  Autoinflammatory bone diseases. Rheum Dis Clin N Am. 2013;39(4):735–49. 4. Roderick MR, Sen ES, Ramanan AV. Chronic recurrent multifocal osteomyelitis in children and adults: current understanding and areas for development. Rheumatology (Oxford). 2017. 5. Sato TS, Ferguson PJ, Khanna G. Primary multifocal osseous lymphoma in a child. Pediatr Radiol. 2008;38(12):1338–41. 6. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC,

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Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426–37. 7. Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH. Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with sweet syndrome in two siblings. J Pediatr. 1989;115(5. Pt 1):730–4. 8. Reichenberger EJ, Levine MA, Olsen BR, Papadaki ME, Lietman SA. The role of SH3BP2 in the pathophysiology of cherubism. Orphanet J Rare Dis. 2012;7(Suppl 1):S5. 9. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100(23):13501–6. 10. Khanna G, Sato TS, Ferguson P.  Imaging of chronic recurrent multifocal osteomyelitis. Radiographics. 2009;29(4):1159–77. 11. Morbach H, Schneider P, Schwarz T, Hofmann C, Raab P, Neubauer H, Duren C, Beer M, Girschick HJ.  Comparison of magnetic resonance imaging and 99mTechnetium-labelled methylene diphosphonate bone scintigraphy in the initial assessment of chronic non-bacterial osteomyelitis of childhood and adolescents. Clin Exp Rheumatol. 2012;30(4):578–82. 12. Hedrich CM, Hofmann SR, Pablik J, Morbach H, Girschick HJ.  Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2013;11(1):47. 13. Haupt R, Minkov M, Astigarraga I, Schafer E, Nanduri V, Jubran R, Egeler RM, Janka G, Micic D, Rodriguez-Galindo C, Van Gool S, Visser J, Weitzman S, Donadieu J, Euro Histio N. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013;60(2):175–84. 14. Gattorno MMA, Goldbach-Mansky R, Aubert P, Ferguson PJ.  Monogenic autoinflammatory syndromes. In: J.H. S, editor. A Clinician’s pearls and myths in rheumatology. London: Springer; 2009. 15. Schnabel A, Range U, Hahn G, Berner R, Hedrich CM. Treatment response and Longterm outcomes in children with chronic nonbacterial osteomyelitis. J Rheumatol. 2017;44(7):1058–65. 16. Beck C, Morbach H, Beer M, Stenzel M, Tappe D, Gattenlohner S, Hofmann U, Raab P, Girschick HJ. Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment. Arthritis Res Ther. 2010;12(2):R74. 17. Borzutzky A, Stern S, Reiff A, Zurakowski D, Steinberg EA, Dedeoglu F, Sundel RP. Pediatric chronic nonbacterial osteomyelitis. Pediatrics. 2012;130(5):e1190–7. 18. Voit AM, Arnoldi AP, Douis H, Bleisteiner F, Jansson MK, Reiser MF, Weckbach S, Jansson AF. Whole-body magnetic resonance imaging in chronic recurrent multifocal osteomyelitis: clinical Longterm assessment may underestimate activity. J Rheumatol. 2015;42(8):1455–62. 19. Vittecoq O, Said LA, Michot C, Mejjad O, Thomine JM, Mitrofanoff P, Lechevallier J, Ledosseur P, Gayet A, Lauret P, le Loet X. Evolution of chronic recurrent multifocal osteitis toward spondylarthropathy over the long term. Arthritis Rheum. 2000;43(1):109–19.

Chapter 108

Bone Pain in Upper Leg, Hip, Lower Back Christian M. Hedrich

An 11-year-old girl developed pain in her right upper leg, hip, and her lower back. Pain gradually worsened and made it impossible for her to walk long distances or participate in sports or other social activities. The patient was not febrile, did not show skin rashes, or other symptoms of systemic inflammation. Neither the patient nor her family members reported pre-existing conditions or chronic disorders. Vaccinations had been tolerated and severe infections had never occurred. Blood work remained normal without signs of systemic inflammation or organ failure. T2-weighted MRI imaging unveiled bone edema in her right iliac bone, the right femur, and tibia, with contrast enhancement in T1-weighted sequences (Fig. 108.1a–c T1 sequences not shown). To exclude tumors or infection, bone biopsies were taken, which showed dense infiltrates of monocytes and neutrophils, lymphocytes and plasma cells (Fig. 108.1d). Bone and blood cultures remained sterile, and PCR amplification screening for bacterial nucleic acids came back positive for mycobacteria other than tuberculosis (MOTT) from paraffin embedded bone tissue. Without performing additional tests, the diagnosis of atypical mycobacteria infection was made. The patient was treated with azithromycin, rifampicin, and ethambutol plus ibuprofen. Clinical symptoms resolved over the following three months, and ibuprofen was discontinued. Pain reoccurred several weeks later, and bone lesions persisted on MRI imaging. For the following three years, the patient C. M. Hedrich (*) Division of Paediatric Rheumatology and Immunology, Children’s Hospital Dresden, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany Department of Women’s & Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust Hospital, Liverpool, UK e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_108

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Fig. 108.1  Whole body MRI (TIRM sequences) of the then 14-year-old patient at first visit in our institution shows increased signal intensity as a sign of bone inflammation in the right humerus, right trochanter (a), right distal femur (b), and the sixth vertebral body (c) (arrows). (d) Bone biopsies unveiled dense infiltrates with neutrophilic granulocytes, monocytes, and lymphocytes as a sign of chronic bone inflammation

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was treated with anti-mycobacterial treatment with intermittent use of NSAIDs. The clinical course was characterized by phases of severe pain and clinical remission. Since bone lesions on MRI tended to persist, the diagnosis of Mendelian susceptibility to mycobacterial infections was made and the now 14-year-old patient was referred to our institution for a second opinion and to discuss stem-cell transplantation for suspected primary immune deficiency. Q1. What is the most likely diagnosis? A. Mycobacterial infection B. Lymphoma C. Chronic nonbacterial osteomyelitis D. Chronic bacterial osteomyelitis E. Neuroblastoma with bone metastases Answer:  The correct answer is C. The patient most likely suffers from chronic nonbacterial osteomyelitis (CNO), an autoinflammatory bone disorder. CNO is almost as common as bacterial osteomyelitis, and may be frequently missed owing to unawareness of health care providers and the absence of diagnostic criteria and/or disease biomarkers [1–3]. CNO covers a wide clinical spectrum with sometimes mild courses of short duration with inflammation of single bones at one end, and chronically active or recurrent bone inflammation with symmetric involvement of multiple bones at the other end (then referred to as chronic recurrent multifocal osteomyelitis (CRMO). Unfortunately, a majority of patients will develop multifocal disease. A likely diagnosis of CNO in the presented patient is supported by the following reasons: i) at least partial response to ibuprofen and flares after discontinuation, ii) lack of response to antibiotic treatment, iii) chronic course without B symptoms, iv) sterile cultures of bone tissue, as well as, v) inflammatory infiltrates of monocytes, neutrophils, lymphocytes and plasma cells in histopathology [1, 2, 4, 5]. Mycobacterial infections are an important differential diagnosis in patients with inflammatory bone lesions, but are unlikely in the reported patient. Mycobacterial bone infection can occur in patients with defects in the interferon/IL-12 axis. Complete IFN-γ receptor defects usually present with more severe clinical pictures and recurrent infections. Incomplete IFN-γ receptor defects may present with a clinical picture similar to the one in the presented patient. However, positive results in MOTT PCR were likely false, since paraffin embedded tissue samples frequently deliver false positive results and should therefore not be utilized for the diagnosis of mycobacterial infections. In this patient, tuberculosis skin tests or interferon-γ release assays (IGRA) [6], had not been performed initially. Malignancies can be excluded based on the chronic course without the development of B symptoms and absence of signs for malignancy in bone biopsies. Other alternative diagnoses to CNO include Langerhans cell histiocytosis and metabolic bone disease (e.g. hypophosphatasia) [1, 2, 4, 5].

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Q2. All of the following diagnostic tests are indicated at this stage, except A. Bone biopsy with MOTT PCR and culture from “fresh” (not paraffin embedded) bone tissue B. Interferon-γ release assay and tuberculosis skin test C. HLA screening and search for bone marrow donor D. Whole body magnetic resonance imaging E. Stool inflammation markers such as calprotectin if patient reports chronic abdominal pain Answer:  The correct answer is C. In light of the initial PCR results, which were positive for MOTT, re-biopsy and direct pathogen detection from fresh tissue by microscopy, cultures, and PCR should be performed. Additionally, indirect tests, including IGRA and tuberculosis skin testing, should be considered. Whole body MRI will help discover clinically asymptomatic lesions, which may affect the choice of treatment e.g. vertebral involvement would trigger more aggressive treatment. Since CNO can be associated with other inflammatory disorders, including severe acne, psoriasis, and inflammatory bowel disease, these should also be considered and excluded if symptoms suggest their presence. Since the patient does not suffer from primary immunodeficiency, HLA screening and matching is not necessary [1, 2, 4, 5]. Q3. Which of the following statements does not correctly complete the following statement: The pathophysiology of chronic nonbacterial osteomyelitis involves… A. Reduced expression of the immune regulatory cytokines IL-10 and IL-19 B. Increased activation of NLRP3 inflammasomes C. Co-existence of innate immune cell infiltrates, lymphocytes and plasma cells in inflames bone tissue D. Autosomal dominant inheritance in most cases E. Pro-inflammatory monocytes with increased TNF-α and IL-6 expression Answer:  The correct answer is D. Though incompletely understood, the pathophysiology of chronic nonbacterial osteomyelitis involves altered activation of mitogen activated protein kinases (MAPK), namely extracellular signal regulated kinases (ERK) 1 and 2, resulting in reduced activation of the transcription factor signaling protein 1, reduced histone phosphorylation, and subsequently impaired expression of the immune regulatory cytokines IL-10 and IL-19 from monocytes. Increased activation of NLRP3 inflammasomes is the result of reduced IL-10 and IL-19 expression and contributes to downstream proinflammatory cytokine expression including; IL-6 and TNF-α, and defines the proinflammatory phenotype of monocytes in CNO. Dysbalanced pro- and antiinflammatory cytokine expression may contribute to osteoclast differentiation and activation and subsequent bone inflammation (Fig. 108.2). While genetic associations with IL10 promoter polymorphisms have been demonstrated, no single gene mutation has been identified that is strong enough to confer disease [1, 2, 4, 5, 7–10].

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Fig. 108.2  In Monocytes from patients with CNO, mitogen activated protein kinases extracellular signal regulated kinases (ERK)1 and 2 fail to be activated, contributing to reduced activation of the transcription factor Sp-1 and impaired epigenetic “opening” of the IL10 and IL19 genes (through reduced phosphorylation of histone H3 at position serine 10). Reduced expression and secretion of IL-10 and IL-19 result in increased NLRP3 inflammasome activation and subsequently increased IL-1β activation and release. Together with the lack of immune regulatory IL-10 and IL-19, increased inflammasome activation results in down-stream pro-inflammatory cytokine expression. Imbalanced expression of pro-and anti-inflammatory cytokine expression may result in increased differentiation and activation of osteoclasts through increased interaction of the RANK receptor and its soluble ligand (RANKL)

Q4. Currently available therapeutic options in chronic nonbacterial osteomyelitis include all of the following, except A. Nonsteroidal anti-inflammatory drugs B. Corticosteroids C. Bisphosphonates D. B cell depletion with rituximab E. Anti-TNF agents Answer:  The correct answer is D.

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Though clinical trials are lacking, case reports and case-series indicate beneficial effects of NSAIDs, steroids, and bisphosphonates in CNO. NSAIDs inhibit the activity of cyclooxygenase enzymes thereby mediating reduced prostaglandin production, which is necessary for osteoclast activation. Furthermore, several NSAIDs have been reported to inhibit inflammasome activation. Corticosteroids also alter prostaglandin generation through the inhibition of phospholipase A.  Furthermore, corticosteroids reduce the expression of transcription factor nuclear factor κappa B NF-ĸB-dependent proinflammatory cytokines. Thus, corticosteroids may be considered to quickly reduce inflammatory activity or as bridging therapy until “classical” disease modifying drugs (DMARDs) begin to work. TNF inhibitors may at least partially restore the balance between pro- and anti-inflammatory cytokines. Lastly, bisphosphonates inhibit osteoclasts and confer immunoregulation effects (Fig.  108.3). Though lymphocytes and plasma cells are characteristic bone infiltrates in CNO, they are rather a secondary phenomenon. Thus, B cell depletion has not been performed in this disease and is unlikely to resolve bone inflammation in a likely monocyte-driven disease [2].

Fig. 108.3  Usually, CNO patients are initially treated with NSAIDs. If patients fail to reach remission or flare, additional treatment may be considered. Corticosteroids can quickly control inflammatory activity. Since a large proportion of patients flare after discontinuation of corticosteroids, they can be used as “bridging therapy” until DMARDs start working. TNF inhibitors and bisphosphonates have been reported efficacious in CNO. In a report suggesting zolendronic acid to be effective in controlling inflammation, patients were concomitantly treated with infliximab. If patients present with spinal involvement, particularly with structural damage, NSAID mono therapy should be skipped and alternative, more aggressive treatments should be considered right away

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Q5. Which of the following conditions is not associated with CNO/CRMO? A. Psoriasis B. Crohn’s disease C. Severe acne D. Atopic dermatitis E. Palmoplantar pustulosis Answer:  The correct answer is D. CNO is associated with other inflammatory conditions, including psoriasis, its subform; palmoplantar pustulosis, inflammatory bowel disease e.g. Crohn’s disease or ulcerative colitis, and severe acne. In adults, a symptom complex involving Synovitis, Acne, Palmoplantar pustulosis, Hyperostosis and Osteitis is referred to as SAPHO syndrome. Since any of these symptoms may also occur in individual pediatric patients with CNO, SAPHO and CNO are considered to be closely related or the same disorder with variable presentation in different age groups. An association has not been reported between atopic dermatitis and CNO [1, 2, 11–13]. Q6. Which of the following statements is not correct? A. Chronic nonbacterial osteomyelitis is a self-limiting disorder B. Vertebral fractures are a possible complication of chronic nonbacterial osteomyelitis C. Chronic disease activity is associated with complications D. Less than 50% of patients flare after initial remission E. Arthritis can be seen in patients with chronic nonbacterial osteomyelitis Answer:  The correct answer is D. Generally, CNO can be seen as a self-limiting disorder and bone inflammation and resulting symptoms may resolve within months or years after the onset of disease. However, symptoms can persist for more than two decades, and chronic courses with persistently high inflammatory activity are associated with arthritis or bone fractures, mostly vertebral compression fractures. While most patients initially respond to treatment (>66% to NSAIDs within the first year), up to half experience a flare within a median of 29 months. In light of potentially severe complications, high flare rates, and high incidence of pain amplification syndromes in these patients, CNO is potentially a much more debilitating disorder than previously suggested [1, 2, 11–14].

Practical Points • Chronic nonbacterial osteomyelitis (CNO) covers a wide clinical spectrum with mild courses of short duration with inflammation of single bones at one end, and chronically active or recurrent bone inflammation with symmetric involvement of multiple bones at the other

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• Lack of response to antibiotic treatment and absence of B symptoms in a chronic course, complete or partial symptomatic response to NSAIDs, flares after discontinuation, sterile cultures of bone tissue, and inflammatory infiltrates in histopathology, support a diagnosis of CNO in a patient with chronic osteomyelitis

References 1. Hedrich CM, Hofmann SR, Pablik J, Morbach H, Girschick HJ.  Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J. 2013;11(1):47. 2. Hofmann SR, Kapplusch F, Girschick HJ, Morbach H, Pablik J, Ferguson PJ, Hedrich CM. Chronic Recurrent Multi-focal Osteomyelitis (CRMO): presentation, pathogenesis and treatment. Curr Osteoporos Rep. 2017;15(6):542–54. 3. Schnabel A, Range U, Hahn G, Siepmann T, Berner R, Hedrich CM. Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children. Rheumatol Int. 2016;36(12):1737–45. 4. Hedrich CM, Hahn G, Girschick HJ, Morbach H. A clinical and pathomechanistic profile of chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis and challenges facing the field. Expert Rev Clin Immunol. 2013;9(9):845–54. 5. Hofmann SR, Roesen-Wolff A, Hahn G, Hedrich CM.  Update: cytokine dysregulation in Chronic Nonbacterial Osteomyelitis (CNO). Int J Rheumatol. 2012;2012:310206. 6. Patel SY, Doffinger R, Barcenas-Morales G, Kumararatne DS. Genetically determined susceptibility to mycobacterial infection. J Clin Pathol. 2008;61(9):1006–12. 7. Hofmann SR, Kubasch AS, Ioannidis C, Rosen-Wolff A, Girschick HJ, Morbach H, Hedrich CM. Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1beta expression and release. Clin Immunol (Orlando, FL). 2015;161(2):300–7. 8. Hofmann SR, Kubasch AS, Range U, Laass MW, Morbach H, Girschick HJ, Hedrich CM. Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO). Rheumatol Int. 2016;36(6):769–79. 9. Hofmann SR, Morbach H, Schwarz T, Rosen-Wolff A, Girschick HJ, Hedrich CM. Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. Clin Immunol (Orlando, FL). 2012;145(1):69–76. 10. Hofmann SR, Schwarz T, Moller JC, Morbach H, Schnabel A, Rosen-Wolff A, Girschick HJ, Hedrich CM.  Chronic non-bacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL-10 expression. Clin Immunol (Orlando, FL). 2011;141(3):317–27. 11. Ferguson PJ, El-Shanti HI.  Autoinflammatory bone disorders. Curr Opin Rheumatol. 2007;19(5):492–8. 12. Ferguson PJ, Sandu M. Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep. 2012;14(2):130–41. 13. Hofmann SR, Schnabel A, Rosen-Wolff A, Morbach H, Girschick HJ, Hedrich CM. Chronic nonbacterial osteomyelitis: pathophysiological concepts and current treatment strategies. J Rheumatol. 2016;43(11):1956–64. 14. Schnabel A, Range U, Hahn G, Berner R, Hedrich C. Treatment response and longterm outcomes in children with chronic nonbacterial osteomyelitis. J Rheumatol. 2017;44(7):1058–65.

Chapter 109

Enterocolitis Followed by Recurrent Sepsis-Like Episodes Tania Siahanidou, Sofia Tantou, and Maria Kanariou

A 20-day-old male infant of Caucasian origin was admitted to neonatal unit after 3  days of diarrhea which became bloody 3  days later. The infant was born by a healthy primigravida mother, at 40 weeks of gestation following an uneventful pregnancy, through cesarean section due to labor dystocia. His birthweight was 3450 grams. Apgar score was 9 and 10 at 1 and 5 minutes respectively. The boy was fed with breastmilk and formula. On admission, the baby was lethargic and severely dehydrated, weighting 2450 g. He presented respiratory distress, abdominal distension, with a core temperature 34.7  °C and metabolic acidosis; pH: 7.11, HCO3: 4.1  mmol/L, base excess: −22 mmol/L. Routine laboratory investigations showed leukocytosis, elevated acute phase reactants, thrombocytopenia and coagulopathy; prothrombin time: 21.6 seconds, fibrinogen: 74 mg/dL, d-dimers: 1.4 μg/mL. Blood, urine, stool and CSF cultures were all negative. The baby was intubated and mechanically ventilated for 24 hours and was also treated with FFP, packed RBC and platelets, inotropes (i.e. dopamine and dobutamine) and IV antibiotics (meropenem plus teicoplanin). He recovered and restarted feeding with an elemental formula, in gradually increasing amounts in combination with total parenteral nutrition (TPN). There was no history of consanguinity between parents or a family history for enteropathy or other chronic disease.

T. Siahanidou First Department of Pediatrics, National & Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece S. Tantou · M. Kanariou (*) Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies, Pediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece

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Q1. Given patient’s history and initial laboratory findings, which of the following diagnostic categories is most probable? A. Disseminated infection B. Cellular and humoral deficiency C. Congenital enteropathy D. Cow’s milk allergy E. Neuroendocrine tumor F. Inborn error of metabolism G. Cystic fibrosis Answer:  The correct answer is A. The most possible diagnosis for a neonate with the above picture is disseminated intravascular coagulation (DIC)), probably by infectious agent. Underlying disorders associated with neonatal diarrhea include: (1) disorders with altered digestion, absorption or transport of nutrients and electrolytes, e.g. disaccharidase deficiency, congenital chloride or sodium diarrhea, pancreatic insufficiency, abetalipoproteinemia or hypobetalipoproteinemia, infectious or allergic enteropathy, enterocyte differentiation and polarization defects as in microvillus inclusion disease, (2) immune dysfunction as in isolated PIDs or those presenting as polyendocrinopathy/e.g. IPEX or IPEX-like syndrome, (3) defects of enteroendocrine cell differentiation as in enteric anendocrinosis/dysendocrinosis, proprotein convertase I deficiency, or neuroendocrine tumors (e.g. neuroblastoma, VIP secreting tumors) [1]. In order to exclude an underlying diagnosis an initial workup for immune deficiency, enteropathy or cystic fibrosis was performed. Serum levels of IgG, IgA, IgM were normal for age while mildly increased IgD levels, elevated IgE levels (74.6 IU/ mL) and specific IgE for cow’s milk protein below 0.35 UA/mL (class 0) were observed. C3, C4 and CH50 were within normal values as well as lymphocyte immunophenotype in peripheral blood. Cystic fibrosis was excluded by normal serum immunotrypsinogen, fecal trypsin and a chloride sweat test. Upper gastrointestinal series and barium enema X-rays were normal and a gastrointestinal endoscopy was scheduled. However, during the next three months the infant presented six more episodes of recurrent fevers, with reducing severity and duration, accompanied with clinical signs of sepsis and increased markers of inflammation (serum CRP up to 12 mg/ dL). The first two flares were presented while the infant was on antibiotics intravenously and on enteral feed with an elemental formula. Again, no pathogen was identified in biological fluids, neither by cultures, nor through molecular investigation. Serology for known congenital infections was also negative. The baby was well-appearing and otherwise normal on examination between episodes, apart from mild hepatosplenomegaly. Repeated full blood counts, blood biochemistry and markers of infection had normal values between flares, apart from intermittent peripheral eosinophilia (eosinophils 200–2,700/μL). Immunologic workup was further expanded, testing specific lymphocyte subpopulation counts in addition to the major lymphocyte populations without pathologic findings. Normal results were given for neutrophil oxidative burst, IRAK4/NF-kB

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signaling, LPS-induced IL-10 production, and integrins expression on leukocytes. Bone marrow biopsy was normal as well. Gastrointestinal histology revealed moderate eosinophilic infiltration of duodenum, mild eosinophilic infiltration of esophagus, gastric mucosa and rectum, and also mild to moderate chronic rectal inflammation. Q2. In view of the patient’s further clinical course with recurrent, rather periodic, febrile episodes accompanied by increased acute phase reactants, but no evidence of infection, what is the most probable diagnosis? A. Disease of immune dysregulation B. Defects effecting the inflammasome C. Early onset inflammatory bowel disease D. Metabolic disease E. Endocrine disease Answer:  The correct answer is B. The rather periodic presentation of fever was a fact against the diagnosis of infection or severe combined immunodeficiency. The elevated acute phase reactants, in association with normal metabolic and endocrine workup, supported the possibility of an autoinflammatory disorder or an early-onset inflammatory bowel disease (EOBD), recently recognized as an autoinflammatory disease without periodic presentation. A defect in inflammasome function is the most common pathomechanism in autoinflammatory disorders [2]. Autoinflammation is a consequence of abnormal, spontaneous inflammasome activation and overproduction of IL-1 family cytokines and IL-18, leading to inflammation, high levels of acute-phase reactants and inflammatory cell death i.e. pyroptosis [3, 4]. Q3. Which of the following tests could make definite diagnosis for this patient? A. Serum Amyloid-A and serum IgD B. Serum levels of TNF-α, IL-1β, IL-6 and IL-18 C. DNA analysis for familial Mediterranean fever D. DNA analysis for hyper-IgD syndrome E. Whole exome sequencing Answer:  The correct answer is E. Serum levels of IL-1β, IL-6 and TNF-α, were normal, measured twice between flares. In this setting, IL-18 levels could be possibly helpful; however they were not assessed in our patient. Serum amyloid A (SAA) was mildly increased: 2.3 mg/dL (reference range: up to 1  mg/dL) and serum IgD levels ranged from 3 to 5  mg/ dL. Genetic testing for familial Mediterranean fever, as well as for hyper-IgD syndrome, showed no relative mutations. At this stage, whole exome sequencing (WES) analysis of the infant and his parents performed and demonstrated a heterozygous NLRC4 c.1022  T  >  C

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(p.Val341Ala) de novo mutation in the patient. This mutation was consistent with the clinical phenotype, confirming the diagnosis of autoinflammation with infantile enterocolitis and sepsis-like events [5]. Q4. Which of the following statements is not true regarding NLRC4 gene mutations? A. Mutations of NLRC4 gene in relation to autoinflammatory diseases in humans is a well-known entity over the last 25 years B. They are gain-of-function mutations, promoting spontaneous formation of the NLRC4 inflammasome C. Clinical presentations are variable even with the same mutation D. Autoinflammation with infantile enterocolitis (AIFEC), familial cold autoinflammatory syndrome 4 (FCAS4) and neonatal-onset multisystem inflammatory disease (NOMID) are three described subtypes Answer:  The correct answer is A. The product of NLRC4 gene, a cytoplasmic CARD domain-containing protein involved in the prevention and control of infections, was initially described in 2001 [6, 7]. It is only since 2014 that mutations of NLRC4 gene were associated with autoinflammatory diseases in humans [5, 8]. They are mostly heterozygous gain-of-­ function mutations, with complete penetrance, promoting spontaneous formation of the NLRC4 inflammasome. Novel germline or somatic mutations have been identified as well [9]. Until now, three NLRC4 inflammasomopathy phenotypes have been described in a small number of patients: autoinflammation with infantile enterocolitis (AIFEC) [5, 8, 10, 11], FCAS4 [12, 13], and NOMID [14]. Q5. Having the WES results with a mutation in the NLRC4, what is the best therapeutic option at this stage? A. Antibiotics B. Blocking the involved cytokines and pathways C. Immunosuppression management D. Anti-inflammatory regimen Answer:  The correct answer is B. Overproduction of IL-1β, leading to fever and organ-specific inflammatory manifestations, can possibly be managed by IL-1/IL-1R pathway blockade. The IL-1β receptor antagonist, anakinra, a human dimeric fusion protein, rilonacept, and a fully human anti-IL-1β monoclonal antibody, canakinumab, have been used for treating patients with NLRC4 mutation [8, 10, 15]. Additional recombinant IL-18 binding protein was shown to be efficacious in a critically ill neonate with NLRC4 mutation-associated enterocolitis which was refractory to corticosteroids, cyclosporine, IL-1β, TNF-α and integrin-inhibition [10]. Patient is now on subcutaneous anakinra (2  mg/Kg/day) with initial good response, without sepsis-like events more than six months now and is under close follow up.

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Q6. All of the following options are among secondary manifestations or complications of NLRC4 mutations, except: A. Macrophage activation syndrome B. Short stature C. Anemia of chronic disease D. Amyloidosis E. Skin manifestations Answer:  The correct answer is D. Early-onset necrotizing enterocolitis in patients with NLRC4 mutations is often accompanied by MAS-like syndrome (pancytopenia, coagulopathy, hyperferritinemia, increased triglycerides, etc.) [5]. Short stature and anemia of chronic disease have also been reported in patients surviving the infantile period [5]. Skin manifestations, including nodular/urticarial rash or arthralgia have been described in these patients presenting with FCAS1 phenotype [12, 13]. No case of amyloidosis related to NLRC4 mutations has been reported so far [9], but the number of cases is low and the duration of follow-up is short. Combination of severe sepsis-like episodes, increased acute phase reactants, absence of any infectious agent in several biological samples, and rather healthy appearance of the infant between attacks, were the “triggers” for investigating for possible autoinflammatory disorder as an underlying disease. Practical Points • Autoinflammatory diseases should be included in the differential diagnosis of recurrent episodes of systemic inflammation, as early as in the neonatal age • NLRC4 mutations can cause life threatening macrophage activation syndrome • Early DNA analysis and identification of the responsible gene is crucial for early diagnosis in order to decide the most appropriate therapy and improve patients prognosis

References 1. Siahanidou T, Koutsounaki E, Skiathitou AV, Stefanaki K, Marinos E, Panajiotou I, Chouliaras G.  Extraintestinal manifestations in an infant with microvillus inclusion disease: complications or features of the disease? Eur J Pediatr. 2013;172(9):1271–5. 2. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar HB.  Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.

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3. Corridoni D, Arseneau KO, Cominelli F. Functional defects in NOD2 signaling in experimental and human Crohn disease. Gut Microbes. 2014;5(3):340–4. 4. Man SM, Kanneganti TD.  Regulation of inflammasome activation. Immunol Rev. 2015;265(1):6–21. 5. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46(10):1135–9. 6. Khameneh HJ, Mortellaro A. NLRC4 gets out of control. Nat Genet. 2014;46(10):1048–9. 7. Zhu G, Chen J, Tian J, Ge L, Xing A, Tang G. Expression of NLRC4 in children with septicaemia and mechanisms of NLRC4 in in vitro cytokine secretion. Mol Med Rep. 2016;14(1):509–14. 8. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–6. 9. Romberg N, Vogel TP, Canna SW.  NLRC4 inflammasomopathies. Curr Opin Allergy Clin Immunol. 2017;17(6):398–404. 10. Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, Surrey LF, Russo P, Sleight A, Schiffrin E, Gabay C, Goldbach-Mansky R, Behrens EM. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139(5):1698–701. 11. Liang J, Alfano DN, Squires JE, Riley MM, Parks WT, Kofler J, El-Gharbawy A, Madan-­ Kheterpal S, Acquaro R, Picarsic J.  Novel NLRC4 mutation causes a syndrome of perinatal autoinflammation with hemophagocytic lymphohistiocytosis, hepatosplenomegaly, fetal thrombotic vasculopathy, and congenital anemia and ascites. Pediatr Dev Pathol. 2017;20(6):498–505. 12. Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K. An inherited mutation in NLRC4 causes autoinflammation in human and mice. J Exp Med. 2014;211(12):2385–96. 13. Volker-Touw CM, de Koning HD, Giltay JC, de Kovel CG, van Kempen TS, Oberndorff KM, Boes ML, van Steensel MA, van Well GT, Blokx WA, Schalkwijk J, Simon A, Frenkel J, van Gijn ME.  Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype. Br J Dermatol. 2017;176(1):244–8. 14. Kawasaki Y, Oda H, Ito J, Niwa A, Tanaka T, Hijikata A, Seki R, Nagahashi A, Osawa M, Asaka I, Watanabe A, Nishimata S, Shirai T, Kawashima H, Ohara O, Nakahata T, Nishikomori R, Heike T, Saito MK. Identification of a high-frequency somatic NLRC4 mutation as a cause of autoinflammation by pluripotent cell-based phenotype dissection. Arthritis Rheumatol (Hoboken, NJ). 2017;69(2):447–59. 15. Sleptsova TVAEI, Savost’yanov KV, Pushkov AA, Bzarova TM, Valieva SI, Lomakina OL, Denisova RV, Isaeva KB, Chistyakova EGE.  Experience of the successful treatment with canakinumab of a patient with NLPC4-associated autoinflammatory syndrome with enterocolitis. Pediatr Pharmacol. 2016;13(2):143–8.

Chapter 110

Recurrent Febrile Attacks, Myalgia and Livedo Reticularis Sezgin Sahin, Amra Adrovic, Kenan Barut, and Ozgur Kasapcopur

An 8-year-old boy was referred due to recurrent febrile attacks associated with myalgia, diarrhea, colicky abdominal pain, severe weight loss (nearly 10  kg in 1 year) and hypertension. He had a history of recurrent febrile episodes with myalgia since 6 years of age, and the last attack had associated with hypertension and abdominal pain as well. The first two attacks were at intervals of 1 year and characterized by myalgia, livedo reticularis and increased acute phase reactants. Her parents were first cousins but there was no similar clinical manifestation in any of his family members. His family reported hydrocephalus secondary to intraventricular hemorrhage when he was 1-year-old. On examination, he was not febrile (T: 37.8  °C), he had mild hypertension (150/100 mmHg). He had a weight: 20 kg which was below third percentile and height: 130 cm, on tenth percentile. There was livedo reticularis on lower legs and arms and diffuse muscle tenderness upon palpation. Diffuse abdominal tenderness without rebound tenderness was also noted. A complete blood count revealed a total leukocyte count of 15,800/μL, platelet count of 316,000/μL and anemia with emoglobin: 9.8 g/dL, hematocrit: 30.9%, and MCV: 70.2 fL. ESR: 30 mm/hr. and CRP level: 5.1 mg/dL were elevated (reference range 95th percentile for height) • Peripheral neuropathy • Renal involvement Our patient was diagnosed as childhood polyarteritis nodosa with the aneurysms in mesenteric and renal arteries plus myalgia, livedo reticularis and hypertension. The peculiar histopathological features of PAN are fibrinoid necrosis of the medium or small arteries walls plus occasional thromboses inside the lumen [3, 5]. Q3. Which one of the following tests is an essential prerequisite for definitive diagnosis? A. Angiography B. Livedo reticularis C. Hypertension D. Myalgia Answer:  The correct answer is A. Presence of either aneurysms, stenosis or occlusion of medium or small sized arteries in CT scan or magnetic resonance angiography or fibrinoid necrosis in histopathological findings is a mandatory criterion for childhood PAN [4]. Q4. Which one of the following vessels is less likely to be involved in the course of the disease? A. Celiac artery B. Superior mesenteric artery C. Glomerular capillaries D. Muscular arteries Answer:  The correct answer is C.

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Polyarteritis nodosa is a medium or small -sized vessel vasculitis. Since vascular inflammation is not seen in arterioles, venules and capillaries, glomeruli are not involved in the course of disease [1, 5]. Q5. What would be the most likely diagnosis, if you realize that the cousin of this patient has developed similar manifestations? A. Cryopyrin-associated periodic syndrome/CAPS B. TNF receptor-associated periodic syndrome/TRAPS C. STING-associated vasculitis onset in infancy/SAVI D. Deficiency of adenosine deaminase-2/DADA2 Answer:  The correct answer is D. In 2014, two group at the same time published their studies that were describing a monogenic autoinflammatory PAN-like disease which was inherited with an autosomal recessive pattern [6, 7]. Deficiency of adenosine deaminase type-2 (DADA2) enzyme was found to be associated with vasculitis of medium and small-sized arteries and responsible for the clinical features. Despite similar manifestations, ischemic or hemorrhagic strokes are reported to be more frequent in DADA2 [8–12]. The past history of the intraventricular hemorrhage when our patient was 1-year-­ old, could be suggestive of DADA2 more than PAN. The following extra features in a PAN patient should direct clinicians to mutation analysis for DADA2: • • • •

Early-onset manifestations Presence of consanguinity Presence of a relative with same clinical picture Ischemic or hemorrhagic stroke

Moreover, 42 of the 81 subjects with DAD2 in the previously published reports, had been diagnosed and treated as PAN before the definite diagnosis [12]. DADA2 is classified both in the category of vasculitis and autoinflammatory diseases. Q6. Mutation in which of the following genes could result in DADA2? A. NLRP3 B. MEFV C. CECR1 D. TRAPS Answer:  The correct answer is C. Decreased enzymatic activity of adenosine deaminase type 2 enzyme via loss-of-­ function mutations in “cat eye syndrome chromosome region 1 gene; CECR1 causes vasculopathy in medium or small-sized arteries [6, 7]. Q7. Which one of the following manifestation or complication is least likely to be encountered in a patient with PAN or DADA2? A. Ischemic stroke B. Glomerulonephritis C. Hemorrhagic stroke D. Mesentery ischemia Answer:  The correct answer is B.

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Both PAN and DADA-2 affect medium or small sized arteries and do not involve arterioles, venules or capillaries. Hence, glomerulonephritis is not seen in the course of the disease [6–12]. Practical Points • Polyarteritis nodosa (PAN) is characterized by fibrinoid necrosis of the vessel wall of small to medium sized arteries • Diagnosis of PAN in children requires demonstration of necrotizing vasculitis by histopathology, aneurysm formation, stenosis, or occlusion by angiography in medium or small -sized arteries, plus one of the following: –– –– –– –– ––

Cutaneous findings such as livedo reticularis, nodules, infarcts Myalgia or tenderness upon palpation Hypertension (>95th percentile for height) Peripheral neuropathy Renal involvement

• The following extra features in a PAN patient should direct clinicians to deficiency of adenosine deaminase type 2: –– –– –– ––

Early-onset manifestations Presence of consanguinity Presence of a relative with same clinical picture Ischemic or hemorrhagic stroke

References 1. Barut K, Sahin S, Kasapcopur O. Pediatric vasculitis. Curr Opin Rheumatol. 2016;28(1):29–38. 2. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11. 3. Lie JT.  Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum. 1990;33(8):1074–87. 4. Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, Buoncompagni A, Lazar C, Bilge I, Uziel Y, Rigante D, Cantarini L, Hilario MO, Silva CA, Alegria M, Norambuena X, Belot A, Berkun Y, Estrella AI, Olivieri AN, Alpigiani MG, Rumba I, Sztajnbok F, ­Tambic-­Bukovac L, Breda L, Al-Mayouf S, Mihaylova D, Chasnyk V, Sengler C, Klein-Gitelman M, Djeddi D, Nuno L, Pruunsild C, Brunner J, Kondi A, Pagava K, Pederzoli S, Martini A, Ruperto N, Paediatric Rheumatology International Trials O. EULAR/PRINTO/PRES criteria for HenochSchonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69(5):798–806. 5. Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol (Berlin, Germany). 2010;25(9):1641–52.

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6. Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes PJ, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom TM, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King MC, Levy-Lahad E. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–31. 7. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911–20. 8. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, Conti G, Marchetti F, Picco P, Tommasini A, Martino S, Malattia C, Gallizi R, Podda RA, Salis A, Falcini F, Schena F, Garbarino F, Morreale A, Pardeo M, Ventrici C, Passarelli C, Zhou Q, Severino M, Gandolfo C, Damonte G, Martini A, Ravelli A, Aksentijevich I, Ceccherini I, Gattorno M. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017;76(10):1648–56. 9. Caorsi R, Penco F, Schena F, Gattorno M. Monogenic polyarteritis: the lesson of ADA2 deficiency. Pediatr Rheumatol Online J. 2016;14(1):51. 10. Garg N, Kasapcopur O, Foster J 2nd, Barut K, Tekin A, Kizilkilic O, Tekin M. Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr. 2014;173(6):827–30. 11. Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, Ekelund M, Jolles S, Harper L, Youngstein T, Gilmour K, Klein NJ, Eleftheriou D, Brogan PA. Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol (Hoboken, NJ). 2016;68(9):2314–22. 12. Sahin S, Adrovic A, Barut K, Ugurlu S, Turanli ET, Ozdogan H, Kasapcopur O.  Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. Rheumatol Int. 2018;38(1):129–36.

Chapter 111

Sudden Dizziness, Somnolence and Diplopia Stefan Berg, Per Wekell, and Anders Fasth

A 12-year-old girl is referred to you as an emergency case. Her father explains how she suddenly became somnolent complaining of dizziness and diplopia two hours before her arrival at the emergency. She has difficulties to sit properly and a tendency to fall towards the right side. She has no headache, nausea or vomiting. The referral records revealed that the general practitioner had followed her for 2 years due to short recurrent fever episodes and continuous mild inflammation with slightly increased CRP (1.7  mg/dL) and ESR (20  mm/hr) between the episodes. Levels of inflammatory markers were not available during fever episodes. Anti-­ nuclear antibodies (ANA) and antineutrophil cytoplasmic antibody (ANCA) were negative at two occasions. She has been otherwise healthy without any history of headache or neurological manifestations. Her growth, development and school performance had been normal. Her family history does not uncover any history of recurrent febrile episodes, stroke or headache including migraine. On examination, her vital signs are normal. Her temperature is 38.1°C and oxygen saturation 94 percent. She is somnolent but oriented to time, place and persons. Glasgow coma scale is 13. Neurological examination shows no clear focality, except diplopia and slight central facial nerve palsy. Her tendency to fall to the right side had disappeared. Blood pressure is 102/75 mmHg. She had a rash on her thigh that is illustrated in Fig. 111.1a. The rest of the examination was normal. An emergency

S. Berg · A. Fasth Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden P. Wekell (*) Department of Pediatrics, NU-Hospital Group, Uddevalla, Sweden Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_111

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a

b

Fig. 111.1 (a) Rash on thigh of a patients with sudden onset dizziness. (b) An emergency MRI scan showed infarction located in the medial part of thalamus

MRI scan revealed an infarction located in the medial part of thalamus on the left side Fig. 111.1b. The laboratory results from the emergency room show hemoglobin: 11.9 g/dL, leukocytes: 4300/μL, with normal absolute neutrophil and lymphocyte count, platelets: 298,000/μL, ESR: 21 mm/h and CRP 2.6 mg/dL. Coagulation variables, electrolytes, liver transferases and creatinine are all normal. Anticoagulation therapy was initiated. Q1. With this limited information, which two of the following diagnoses could best explain the patient’s symptoms? 1. Polyarteritis nodosa (PAN) 2. Granulomatosis with polyangiitis (GPA) formerly known as Wegener’s granulomatosis 3. Systemic lupus erythematosus (SLE) 4. Sarcoidosis 5. Deficiency of adenosine deaminase 2 (DADA2) 6. Primary angiitis of the central nervous system A. B. C. D. E.

1, 3 1, 4 4, 5 1, 5 2, 4

Answer:  The correct answer is D. The history of longstanding inflammation and the type of rash makes an inflammatory disease the most likely etiology of her stroke. Both polyarteritis nodosa (PAN) and deficiency of adenosine deaminase 2 (DADA2) can explain the patient’s symptoms and signs, and these two are difficult to differentiate on clinical grounds. PAN is a vasculitis of small and medium-sized arteries and is mainly seen in adulthood, but childhood PAN does exist. Further diagnostic workup for PAN includes angiography and/or biopsy. Pediatric classification criteria have been developed for PAN [1], that include as mandatory criteria: histology (necrotizing vasculitis in medium or small-sized arteries) or angiographic abnormalities (aneu-

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rysm, stenosis or occlusion of a medium or small sized artery), plus at least one of the following five: (1) skin involvement (subcutaneous nodules, livedo reticularis, superficial ulcers, peripheral tissue necrosis), (2) myalgia or muscle tenderness, (3) hypertension, (4) peripheral neuropathy and (5) renal involvement. The clinical and genetic bases of deficiency of adenosine deaminase 2 (DADA2) was first described by two independent groups in 2014 [2, 3]. A study by Navon Elkan et  al. described familial cases previously categorized as early onset PAN [2]. Both groups described a recessive inheritance for DADA2. So far there is no established clinical criteria for DADA2, but the most important clinical features in these early studies were livedo reticularis/racemosa, stroke/transient ischemic attack (TIA), vasculitis, recurrent fever episodes and increased inflammatory markers especially during fever episodes. Some patients had hepatosplenomegaly, ophthalmologic involvement, lymphopenia and low serum IgM or IgG. There is significant clinical overlap between PAN and DADA2. Many of cases of DADA2 have livedo racemosa/reticularis in contrast to PAN, where subcutaneous nodules are a more common skin manifestation [4]. Stroke, recurrent fever episodes and earlier onset of symptoms are more indicative of DADA2 than PAN, but cannot distinguish between the two conditions. Neurosarcoidosis is not a likely diagnosis as it is not associated with livedo racemosa/reticularis. Furthermore, there is a lack of other typical features of sarcoidosis such as lymph node enlargement and lung involvement. Patients with Granulomatosis with polyangiitis (GPA) are usually ANCA positive and often present with the classical triad of kidney, upper and lower respiratory tract involvement. Systemic lupus erythematosus (SLE) may present with many faces, but is almost always ANA positive. Primary angiitis of the central nervous system (PACNS) is a primary vasculitis involving only CNS with no systemic manifestations and it is therefore not likely considering the girl’s history of fever, inflammation and a skin rash. Q2. Which of the following conditions are parts of the expanding phenotype of DADA2? 1. Autoimmunity 2. Immunodeficiency 3. Hematological manifestations 4. Renal failure 5. Pulmonary manifestations A. B. C. D. E.

1, 2 2, 3 3, 4 4, 5 2, 4

Answer:  The correct answer is B.

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DADA2 was in the initial description associated with low IgG, low IgM and varying degrees of lymphopenia, as well as a clinical phenotype with recurrent bacterial and viral infections [3]. More recent studies have described a clinical picture resembling pure red cell aplasia [5]. Schepp et  al. found a broad phenotype in patients with DADA2, including 11 patients with DADA2 in a cohort of 181 patients with antibody deficiency [6]. Q3. You are still not sure if the patient has DADA2 or PAN and realize that a genetic analysis may solve your diagnostic dilemma. Which gene should the genetic analyses focus on? A. ADA B. CECR1 C. NOD2 D. RPS19 Answer:  The correct answer is B. DADA2 is an autosomal recessive disease caused by loss-of-function mutations in CECR1 gene [2, 3]. So far, 41 sequence variants have been found in this gene. Sequence variants in ADA, NOD2 and RPS19 are responsible for severe combined immunodeficiency (SCID) due to ADA deficiency, early-onset sarcoidosis (Blau syndrome) and pure red cell aplasia, respectively. Q4. You are informed that the genetic analyses will take several months. Therefore, you consider if there are any other analyses that may support the diagnoses of DADA2. Which statement is correct? A. High ADA1 is serum will support the diagnosis of DADA2 B. No detectable ADA1 in serum will support the diagnosis of DADA2 C. High ADA2 in serum will support the diagnosis of DADA2 D. Undetectable ADA2 in serum will support the diagnosis of DADA2 E. No, genetic analyses are the only way to support the diagnosis of DADA2 Answer:  The correct answer is D. DADA2 is caused by mutation in the gene that encodes for ADA2 [2, 3]. ADA2 is mainly present in the extracellular space in contrast to ADA1 that is mainly present in the cytosolic space [3]. Measurement of ADA2 in serum can be a marker of DADA2 and can even be used to determine if a novel mutation is pathogenic or not. Heterozygotes have about 50% of ADA2 compared to normal controls. Deficiency of ADA1 causes SCID. Q5. What is the core cell type in the pathogenesis of the disease? A. Macrophage type M1 B. Macrophage type M2 C. T cells D. B cells Answer:  The correct answer is A.

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The initial studies of showed a polarization of monocyte in favor of proinflammatory M1 macrophages and a decrease in the anti-inflammatory M2 macrophages [3]. DADA2 is mainly an autoinflammatory disease, yet with an expanding phenotype including hematological features. Q6. What is the best treatment option in this patient? A. Azathioprine B. Anticoagulation C. TNF-blockade D. Methotrexate E. Cyclophosphamide F. Corticosteroids Answer:  The correct answer is C. Case series have reported promising results with TNF-blockade to prevent new episodes of stroke [2, 4, 7]. Symptom-free individuals with biallelic mutations have been found in family investigations [7]. Whether or not to treat these symptom-free individuals with mutations is yet to be settled [7]. Anticoagulation is an issue of debate and the main concern is the risk of intracerebral bleeding. Azathioprine seems to be less effective than TNF-blockade in DADA2. Methotrexate as single therapy is not effective, but may be used in combination with TNF-blockade to reduce the risk of antibody development against monoclonal TNF-inhibitors. Corticosteroids are effective but the long-term side effects limit their use. Q7. Which treatment would you consider if a patient with DADA2 develops severe anemia and/or immunodeficiency? A. Plasma therapy B. Hematopoietic stem cell transplantation C. Enzyme replacement D. Gene therapy Answer:  The correct answer is B. TNF-blockade is usually an effective treatment of the vascular and inflammatory symptoms, but less effective in treating the hematological and immunological manifestations. A multicenter study of patients with severe hematological and immunological phenotype found a good response to hematopoietic stem cell transplantation (HSCT) [8]. Treatment with fresh-frozen plasma has been tried and it seems to be effective, but owing to the short half-time is not feasible. Enzyme replacement and gene therapy may be options in the future.

Practical Points • Deficiency of adenosine deaminase 2 (DADA2) is a autosomal recessive disease caused by mutations in CECR1 • Mutations in CECR1 cause a deficiency of the enzyme adenosine deaminase type 2 (ADA2)

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• DADA2 phenotype has a wide spectrum and is characterized by the presence of three main features: (1) vascular inflammation, (2) immunodeficiency, and (3) coagulopathy, that may or may not overlap in the individual patient • The vascular-inflammatory manifestations include livedo reticularis/racemosa, stroke, vasculitis, recurrent fever episodes and increased inflammatory markers • The risk for stroke is high in DADA2 • The phenotype may be almost indistinguishable to polyarteritis nodosa (PAN) • TNF-blockade is an effective treatment for the vasculitis and inflammatory manifestations • Patients with severe disease especially with hematological manifestations and immunodeficiency may benefit from HSCT

References 1. Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, Buoncompagni A, Lazar C, Bilge I, Uziel Y, Rigante D, Cantarini L, Hilario MO, Silva CA, Alegria M, Norambuena X, Belot A, Berkun Y, Estrella AI, Olivieri AN, Alpigiani MG, Rumba I, Sztajnbok F, Tambic-­ Bukovac L, Breda L, Al-Mayouf S, Mihaylova D, Chasnyk V, Sengler C, Klein-Gitelman M, Djeddi D, Nuno L, Pruunsild C, Brunner J, Kondi A, Pagava K, Pederzoli S, Martini A, Ruperto N, Paediatric Rheumatology International Trials O. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69(5):798–806. 2. Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes PJ, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom TM, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King MC, Levy-Lahad E. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–31. 3. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-­ Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911–20. 4. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, Conti G, Marchetti F, Picco P, Tommasini A, Martino S, Malattia C, Gallizi R, Podda RA, Salis A, Falcini F, Schena F, Garbarino F, Morreale A, Pardeo M, Ventrici C, Passarelli C, Zhou Q, Severino M, Gandolfo C, Damonte G, Martini A, Ravelli A, Aksentijevich I, Ceccherini I, Gattorno M. ADA2 deficiency

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(DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017;76(10):1648–56. 5. Hashem H, Egler R, Dalal J.  Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol. 2017;39(5):e293–e6. 6. Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Grimbacher B. Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis Rheumatol (Hoboken, NJ). 2017;69(8):1689–700. 7. Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, Ekelund M, Jolles S, Harper L, Youngstein T, Gilmour K, Klein NJ, Eleftheriou D, Brogan PA. Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol (Hoboken, NJ). 2016;68(9):2314–22. 8. Hashem H, Kumar AR, Muller I, Babor F, Bredius R, Dalal J, Hsu AP, Holland SM, Hickstein DD, Jolles S, Krance R, Sasa G, Taskinen M, Koskenvuo M, Saarela J, van Montfrans J, Wilson K, Bosch B, Moens L, Hershfield M, Meyts I. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood. 2017;130(24):2682–8.

Chapter 112

Recurrent Chest Pain Per Wekell, Anders Fasth, and Stefan Berg

A previously healthy 8-year-old boy has left sided chest pain and low-grade fever for the second time. The first time the family sought medical advice at the emergency room at the second day of pain and fever. He was admitted to the pediatric ward and underwent a broad medical evaluation. The chest x-ray showed a slightly enlarged heart. The lungs were clear and no pleural effusion was observed. Electrocardiography showed minor diffuse ST segment abnormalities and a propensity to low voltage in all leads. Echocardiography was normal except that one centimeter of pericardial fluid had accumulated. Inflammatory markers revealed CRP 4.3 mg/dL and ESR 56 mm/hr. Serum creatinine, ALT and AST were within normal range. ANA and anti-dsDNA were negative. Interferon-γ assay for tuberculosis (QuantiFERON®) was negative. Troponin T (TnT) and creatine kinase-MB (CK-­ MB) came back normal. The family is of Lebanese origin and there was no history of recurrent febrile episodes, inflammatory disorders or pericarditis among first-­ degree relatives. He was diagnosed with acute pericarditis, most probably of viral etiology. He was treated with cyclooxygenase-inhibitors and his condition improved during the next few days at the ward. At his first clinical visit a week later electrocardiography and echocardiography were normal. CRP and ESR had decreased to 1.6 mg/dL and 29 mm/hr., respectively. Pending viral PCR from nose swab came back negative for coxsackie B virus, adenovirus, enteroviruses, cytomegalovirus, and influenza virus. Acute phase viral serology was negative for the

P. Wekell (*) Department of Pediatrics, NU-Hospital Group, Uddevalla, Sweden Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden e-mail: [email protected] A. Fasth · S. Berg Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_112

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same viruses. As a result of his positive development the pediatricians decided to continue Cox-inhibitors and scheduled him for an outpatient appointment at the pediatric cardiologist in 8 weeks. After being well for five weeks, he returns to the emergency ward because of sharp left-sided chest-pain that improved on sitting or leaning forward. He is diagnosed with a second episode of pericarditis indicated by low amplitude ECG.  CRP was 5.2 mg/dL and ESR 53 mm/h. Echocardiography including cardiac function was normal. Serum TnT was normal on arrival, at six and at twelve hours. On physical examination, a friction rub was heard, with a heart rate of 110 bpm and blood pressure of 90/45 mmHg. Physical examination was otherwise normal. He was once again admitted to the pediatric ward for further observation, evaluation and treatment. Q1. Which of following entities is more compatible with his condition? A. Acute pericarditis B. Chronic pericarditis C. Perimyocarditis D. Recurrent pericarditis Answer:  The correct answer is D. This patient has recurrent pericarditis with a second episode of pericarditis after a symptom-free interval of 5 weeks [1]. Both episodes were compatible with acute pericarditis with a clinical picture of left-sided chest pain, pericardial friction rub, changes on ECG and increased level of CRP. Proposed diagnostic criteria that were developed for recurrent pericarditis in adults are considered relevant also for children (Table 112.1) [1, 2]. The patient does not fulfill the definition of chronic pericarditis, as the latter by definition, lasts continuously for more than three months [1]. The patient was evaluated for myocarditis at admission during both the first and second episodes without any support for myocardial damage [2]. Q2. You are consulted to advice on treatment in this situation: Which treatment do you recommend when the patient relapses on the initial treatment with cyclooxygenase-inhibitors? A. Colchicine B. Colchicine and Cox-inhibitors Table 112.1  Diagnostic criteria for recurrent pericarditis Clinical history compatible with a documented first attack of acute pericarditis with the following signs. The first attack should be followed by a symptom-free interval of at least 4–6 weeks. There should be evidence of recurrence of pericarditis manifested by recurrent pain compatible with pericarditis and at least one of the following signs:  Pericardial friction rub  Changes on electrocardiography  Echocardiographic evidence of new or worsening pericardial effusion  Elevation in the white-cell count, erythrocyte sedimentation rate, or C-reactive protein level Adopted and modified from from Imazio et al. [1]

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C. Corticosteroids D. Corticosteroids and Cox-inhibitors Answer:  The correct answer is B. The first level treatment for acute pericarditis is a COX-inhibitor [2]. In case of recurrence, addition of colchicine should be considered [2]. Data on children is limited but at least one study supports the observation that adjuvant treatment with colchicine is associated with a significant decrease in the number of recurrences [3]. In adults, the efficacy of colchicine in combination with NSAID in preventing relapses was clearly shown in randomized controlled studies for both acute [4], and recurrent pericarditis [5]. Corticosteroids are not recommended at this point. He was treated with colchicine and NSAID as you recommended and three days later his pain is gone and the friction rub has disappeared. The heart rate is 108 bpm, blood pressure 98/67 mmHg and the respiratory rate is 25. Physical examination and TnT are normal. Q3. The attending physician wants your advice whether he can discharge him or not? Which statement is correct? A. He can be discharged as he improved on the treatment and the friction rub has disappeared. B. He needs to have an echocardiography of his heart to exclude pericardial fluid C. He needs to have an electrocardiography to exclude arrhythmia, myocarditis and sign of pericardial effusion D. He needs to have an echocardiography to exclude pericardial fluid and electrocardiography to exclude arrhythmia and sign of myocarditis Answer:  The correct answer is D. In this situation, the patient needs an echocardiography to exclude pericardial effusion as fading of the friction rub does not exclude pericardial fluid, rather the friction rub may vanish both with the disappearance and with the accumulation of fluid. It is also important to note that a substantial proportion of patients with pericardial effusion are asymptomatic [2]. He needs an electrocardiography to assess left ventricular function to rule out signs of myocarditis as well as overt or impending signs of arrhythmias. The exclusion of myocarditis is supported by the normal TnT. Three months later when you are on leave, his parents contact the department because he has left-sided chest pain again. One of your colleagues examined him and detected that he has a pericardial friction rub, general ST-segment elevation on electrocardiography, but no pericardial effusion on echocardiography. Laboratory analyses show CRP of 3.8 mg/dL and ESR of 44 mm/hr. In summary, he has his third episode when on colchicine and Cox-inhibitors for three months. In this situation, your colleague started adjuvant treatment with corticosteroids in response to his third relapse. He started with a dose of 30 mg prednisolone per day (1 mg/kg/day), which is tapered during 6 weeks. Initially he responded well with relief of pain and normalization of inflammatory markers.

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Four weeks into the tapering of prednisolone the family contacts you as he developed left sided chest pain yet again. At this point, he is on 10 mg (0.3 mg/kg/ day) of prednisolone. After talking to him and his parents you are convinced that he complies with the prescribed medication before and after the initiation of glucocorticoids. Your assessment confirms your suspicion that he has relapsed with pericarditis without pericardial fluid for the fourth time. At your examination, you register that he is cushingoid with a blood pressure of 125/87 mm Hg. Q4. What treatment do you suggest, when he relapses on colchicine, NSAID and corticosteroids? A. Continue with an increase in the dose of corticosteroids B. IL-1 blockade C. Pericardiectomy D. TNF blockade Answer:  The correct answer is B. If available, IL-1 blockade is the preferred treatment in this situation [4]. Increasing the dose of corticosteroids in a boy that already is Cushingoid and has an increased blood pressure, above the 95th percentile for his age, is not recommended. Pericardiectomy is further down the list of treatment options in recurrent pericarditis. TNF-blockade is rarely used in in recurrent pericarditis, although a good response has been described. You decide to start treatment with IL-1 blockade. On your way home that day, you reflect upon the fact that after your colleague started glucocorticoids and the patient relapsed after three weeks when he was on 10 mg of prednisolone. You know that the role of corticosteroid therapy in recurrent pericarditis is controversial. Q5. Which two of the following statement is correct regarding the role of corticosteroids in recurrent pericarditis? 1. Corticosteroids is an effective treatment in recurrent pericarditis and can be given without hesitation, although even minimal doses need to be tapered 2. Corticosteroid use should be restricted in children as side effects are particularly deleterious to growth. If necessary a minimal effective dose should be sought 3. Pretreatment with corticosteroids is essential for the efficacy of colchicine in preventing relapses in recurrent pericarditis 4. Studies have indicated that corticosteroid-treated patients experienced more recurrences then those without A. 1, 2 B. 2, 3 C. 2, 4 D. 3, 4 Answer:  The correct answer is C. It is well known that treatment with corticosteroid should be avoided in children if possible, taken into account their troublesome side effect on growth. If used in

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recurrent pericarditis the minimal effective dose should be sought by slow tapering [1, 2]. In adults, it is has been shown that relapses are more common in patients treated for recurrent pericarditis with glucocorticoids [6, 7]. In the latest guidelines from the European Society of Cardiology, corticosteroids are not recommended in children due to the severity of the side effects, unless there are specific indications such as autoimmune disease [2]. In a retrospective study from 2016, children showed a similar pattern as in adults, where corticosteroid-treated patients experienced more recurrences, side effects and disease-related hospitalization compared to those who not [3]. Furthermore, pretreatment with corticosteroids may attenuate the efficacy of colchicine in preventing recurrent pericarditis [1, 8]. Q6. Which statement is true regarding the long-term prognosis and healthcare needs of children with recurrent pericarditis? 1. The long-term prognosis for children with recurrent pericarditis is generally good, although quality of life and physical functioning can be severely affected by repeated recurrences and glucocorticoid dependence 2. The long-term prognosis for children with recurrent pericarditis is troublesome, mainly because they have a high risk of developing chronic constrictive pericarditis 3. The high rate of relapses, risk of cardiac tamponade and the risk of developing transient pericardial constriction makes long-term follow-up essential 4. The unpredictable course of recurrent pericarditis makes long-term follow-up inefficient and these patients are best cared for on emergency bases, considering the high rate of relapses, risk of cardiac tamponade and transient pericardial constriction A. 1, 2 B. 3, 4 C. 2, 4 D. 1, 3 Answer:  The correct answer is D. The long-term prognosis for children with recurrent pericarditis is generally good, despite that quality of life and physical functioning can be severely affected by frequent recurrences and glucocorticoid dependence [2, 3]. High rate of relapses, risk of cardiac tamponade and the risk of developing transient pericardial constriction makes long-term follow-up essential. The risk of developing chronic constrictive pericarditis is very low in idiopathic recurrent pericarditis [2]. Practical Points • Recurrent pericarditis is diagnosed in a patient with acute pericarditis relapse after a symptom-free interval of 4–6 weeks or longer • First-line treatment for recurrent pericarditis is cycloxygenase-inhibitors and colchicine

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• Corticosteroid should be avoided in children due to their adverse sideeffects, increased risk of relapse and effects on growth • Long-term prognosis for children with recurrent pericarditis is generally good

References 1. Imazio M, Lazaros G, Brucato A, Gaita F. Recurrent pericarditis: new and emerging therapeutic options. Nat Rev Cardiol. 2016;13(2):99–105. 2. Adler Y, Charron P, Imazio M, Badano L, Baron-Esquivias G, Bogaert J, Brucato A, Gueret P, Klingel K, Lionis C, Maisch B, Mayosi B, Pavie A, Ristic AD, Sabate Tenas M, Seferovic P, Swedberg K, Tomkowski W, Achenbach S, Agewall S, Al-Attar N, Angel Ferrer J, Arad M, Asteggiano R, Bueno H, Caforio AL, Carerj S, Ceconi C, Evangelista A, Flachskampf F, Giannakoulas G, Gielen S, Habib G, Kolh P, Lambrinou E, Lancellotti P, Lazaros G, Linhart A, Meurin P, Nieman K, Piepoli MF, Price S, Roos-Hesselink J, Roubille F, Ruschitzka F, Sagrista Sauleda J, Sousa-Uva M, Uwe Voigt J, Luis Zamorano J, European Society of C. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36(42):2921–64. 3. Imazio M, Brucato A, Pluymaekers N, Breda L, Calabri G, Cantarini L, Cimaz R, Colimodio F, Corona F, Cumetti D, Cuccio CD, Gattorno M, Insalaco A, Limongelli G, Russo MG, Valenti A, Finkelstein Y, Martini A. Recurrent pericarditis in children and adolescents: a multicentre cohort study. J Cardiovasc Med (Hagerstown). 2016;17(9):707–12. 4. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D, Forno D, Ferro S, Maestroni S, Belli R, Trinchero R, Spodick DH, Adler Y, Investigators I. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013;369(16):1522–8. 5. Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, Ghisio A, Belli R, Trinchero R. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med. 2005;165(17):1987–91. 6. Imazio M, Brucato A, Cumetti D, Brambilla G, Demichelis B, Ferro S, Maestroni S, Cecchi E, Belli R, Palmieri G, Trinchero R. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation. 2008;118(6):667–71. 7. Lotrionte M, Biondi-Zoccai G, Imazio M, Castagno D, Moretti C, Abbate A, Agostoni P, Brucato AL, Di Pasquale P, Raatikka M, Sangiorgi G, Laudito A, Sheiban I, Gaita F. International collaborative systematic review of controlled clinical trials on pharmacologic treatments for acute pericarditis and its recurrences. Am Heart J. 2010;160(4):662–70. 8. Artom G, Koren-Morag N, Spodick DH, Brucato A, Guindo J, Bayes-de-Luna A, Brambilla G, Finkelstein Y, Granel B, Bayes-Genis A, Schwammenthal E, Adler Y. Pretreatment with corticosteroids attenuates the efficacy of colchicine in preventing recurrent pericarditis: a multi-­ centre all-case analysis. Eur Heart J. 2005;26(7):723–7.

Chapter 113

Irregular Recurrent Fever Per Wekell, Anders Fasth, and Stefan Berg

A 13-year-old-boy referred to you due to repeated non-regular febrile episodes since he was 6  years old. Before the age of 10  years, his episodes went on for 7–10 days, associated with muscular pain, abdominal pain, vomiting and pharyngitis. There is no skin rash or periorbital edema during the episodes. On a few occasions, his episodes have been associated with left or right sided chest pain. Inflammatory markers during the episodes are increased with a CRP of 8.9–16.4 mg/ dL and SAA >300  mg/L, the upper limit of SAA at the laboratory. During the clinical-­visit he recalls that he has had a few episodes during the last six-month. He also says that he gets fever after intense soccer practice. The exercise related episodes last for 2–3 days and are accompanied by mild sore throat without skin rash. When he decreased his soccer practice, he did not develop fever in a predictable way. There is no history of hearing loss. Attacks are not associated with diarrhea, skin rash or triggered by cold or immunization. There is no history of recurrent febrile episodes or any other inflammatory disorders among his first-degree relatives.

P. Wekell (*) Department of Pediatrics, NU-Hospital Group, Uddevalla, Sweden

Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden A. Fasth · S. Berg Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Rheumatology and Immunology, Queen Silvia Children’s Hospital, Gothenburg, Sweden

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Q1. Intrigued by this history you plan the next step of your investigation. All of the following evaluations are indicated, except A. Clinical examination during a febrile episode B. Inflammatory markers measurement outside attacks C. A fever diary with documentation of symptoms, signs and exercise D. CT scan of thorax due to left side chest pain Answer:  The correct answer is D. This question highlights the importance of assessing patients with fever syndromes during an episode. This will allow you to focus on key features of the different diseases in your clinical assessment. Analyzing inflammatory markers outside episodes, e.g. SAA, gives you information about the type of disease you are dealing with and a clue to the future risk of developing amyloidosis. Proper documentation of the fever episodes is always helpful in evaluation of patients with fever syndrome. You manage to see the boy three months later, two days into an episode. Inflammatory markers between episodes have come back normal that are CRP and SAA. The mother brings you the fever diary, which shows that he had one fever episode of 8 days six weeks ago in addition to the present one. That fever episode was associated with a sore throat, abdominal pain, muscular pain, and vomiting. He complains of sore throat and muscular pain, but also left sided chest pain that increases during inspiration. On physical examination, he is febrile with a temperature of 39.5 °C, he complains of fatigue without compromised respiration or circulation. He is red and swollen in his pharynx and has cervical lymphadenitis. On palpation, the abdomen is soft without pain, enlarged liver or spleen. Chest examination reveals decreased breath sounds and dull percussion over the base of the left lung and normal heart sounds. Electrocardiography, echocardiography and serum troponin are normal and CRP is 13.4 mg/dL. Chest X-ray shows normal heart but one centimeter of pleural fluid on the left side. On follow-up, a week later he is all well again. At this point you are not able to make a clinical diagnosis and at the same time you find it difficult to exclude that he has a classical monogenic periodic fever syndrome. Q2. Which of the following genes is most difficult to exclude to underlie his condition? A. NLRP3 -> cryopyrin-associated periodic syndrome (CAPS) B. MEFV -> familial Mediterranean fever (FMF) C. MVK -> mevalonate-kinase deficiency (MKD) D. TNFRSF1A -> TNF receptor-associated periodic fever syndrome (TRAPS) Answer:  The correct answer is D. Among the classical monogenic periodic fever syndromes, TNF receptor-­ associated periodic fever syndrome (TRAPS) is the most difficult condition to exclude in this case, as his episodes are long (>6 days) associated to myalgia, chest pain and abdominal pain that are all in keeping with TRAPS [1, 2]. He lacks skin

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rash, including the typical migratory painful erythema seen in TRAPS. There are no affected relatives, which is an important information taken into account that TRAPS is an autosomal dominant disease, however, lack of family history does not exclude TRAPS as he may have a de novo mutation. Exercise induced episodes have been described in TRAPS, but vomiting is considered atypical. Familial Mediterranean fever can be excluded on the basis of the length of the episodes [3–5]. Cryopyrin-associated periodic syndrome (CAPS) is not likely as there are no typical CAPS-features, such as urticarial rash, sensorineural hearing loss and conjunctivitis but also by the presence of abdominal pain which is unlikely in CAPS [2, 6]. History is not compatible with mevalonate-kinase deficiency, including the late onset (>1 year), presence of chest pain as well as the absence of skin rash, aphthous stomatitis and diarrhea [2, 5]. In this case the laboratory offered analyses of all the four classical monogenic periodic fever genes for the same price as one, but analysis of NLRP3, MEFV, MVK and TNFRSF1A were negative. The method used excluded somatic mosaicism down to a frequency of 4 percent of the analyzed cell population. Q3. What would you tell him and his parents when they ask if he has a periodic fever syndrome or not? A. Because the genetic analyze is negative you inform the parents that he does not have a periodic fever syndrome B. As the genetic analyze is negative you inform the parents that his condition is most likely due to periodic fever aphthous stomatitis pharyngitis adenitis C. You tell the parents that many children with periodic fever syndrome have conditions that are non-classifiable according to clinical features and/or genetic analyses, and that this is most probable the case with their son’s condition D. You tell the parents that you do not have any idea what he has and that you are sorry to tell the family that the investigation has failed Answer:  The correct answer is C. Many patients with periodic fever syndrome have conditions that cannot be classified according to clinical features or genetic analyzes, but data on this group are sparse for children [7]. He probably has an unclassified periodic fever syndrome. There are many names for unclassified periodic fever syndrome including; unclassified systemic autoinflammatory disease (UNC-SAID or uSAID), autoinflammation of unknown cause, systemic undifferentiated recurring fever syndrome (SURFS), undifferentiated autoinflammatory disorder and autoinflammation of unknown cause. The degree of inheritance varies among non-classifiable autoinflammatory disorders from no inheritance to autosomal dominant. Patients may have recurrent fevers or chronic inflammation, together with different combinations of arthralgia or arthritis, mouth ulcers, lymphadenopathies, conjunctivitis, rashes, splenomegaly, hepatomegaly and abdominal pain.

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He and his mother understand your explanation and accept that he most probable has a non-classifiable periodic fever syndrome. Q4. What is the best initial treatment for this condition? A. Colchicine B. IL-1 blockade C. TNF-blockade D. Glucocorticoids Answer:  The correct answer is A. Many cases of unclassified periodic fever syndrome respond to colchicine and this is the most reasonable first-line treatment in this case. Colchicine is a safe drug in standard dosage, but the efficiency of the treatment needs to be evaluated. It is possible that he would respond to IL-1 blockade [7], but at this stage colchicine is preferred because of oral administration of colchicine, the low cost and possible side effects that accompanies IL-1 blockade. TNF-blockade is rarely indicated in children with periodic fever syndrome in contrast to children with non-systemic JIA. Repeated and long-term treatments with glucocorticoids are associated with too many side effects including weight gain, short stature, osteoporosis, stomach ulcer and increased blood glucose. Second-line treatment in this case would be IL-1 blockade, for which the efficacy in unclassified autoinflammatory conditions has been observed in a small cohort of adult patients [7]. He responded well to colchicine and is today without any obvious fever episodes. He resumed his soccer practice with no associated inflammatory episode. Practical Points • Non-classifiable periodic fever syndromes are common • Patients may have recurrent fevers or continuous chronic inflammation, together with different combinations of arthralgia/arthritis, mouth ulcers, lymphadenopathies, conjunctivitis, rashes, pleuritic pain, splenomegaly, hepatomegaly and abdominal pain • Inheritance varies from no apparent pattern to autosomal dominant inheritance • Many patients respond to colchicine as a reasonable first-line treatment

References 1. Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, Frenkel J, Anton J, Kone-­ Paut I, Cattalini M, Bader-Meunier B, Insalaco A, Hentgen V, Merino R, Modesto C, Toplak N, Berendes R, Ozen S, Cimaz R, Jansson A, Brogan PA, Hawkins PN, Ruperto N, Martini A, Woo P, Gattorno M, Paediatric Rheumatology International Trials Organisation tE, the Eurofever P. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160–7.

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2. Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G, Woo P, Kone-Paut I, Dewarrat N, Cantarini L, Insalaco A, Uziel Y, Rigante D, Quartier P, Demirkaya E, Herlin T, Meini A, Fabio G, Kallinich T, Martino S, Butbul AY, Olivieri A, Kuemmerle-Deschner J, Neven B, Simon A, Ozdogan H, Touitou I, Frenkel J, Hofer M, Martini A, Ruperto N, Gattorno M, Paediatric Rheumatology International Trials O, Eurofever P. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799–805. 3. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85. 4. Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N, Cakar N, Duzova A, Kasapcopur O, Elhan AH, Doganay B, Ekim M, Kara N, Uncu N, Bakkaloglu A. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395–8. 5. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2013;10(3):135–47. 6. Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R, Hoffman HM, Kastner DL.  The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56(4):1273–85. 7. Harrison SR, McGonagle D, Nizam S, Jarrett S, van der Hilst J, McDermott MF, Savic S.  Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology. JCI Insight. 2016;1(6):e86336.

Chapter 114

Fever, Headache and Photophobia Crescent Darius Cossou-gbeto, Leila Dangou, Medeton Grâce Hounkpe, and Josephiel Fortunato

A 14-year-old boy is referred by his parents for fever associated with chills, headache, and photophobia. He has a history of repetitive infections as unspecified meningitis, pneumonia and ear infections at the age of 4 and 6 years old. Members of his immediate family (father, mother, two brothers, and a sister) are in apparent good health. On examination he was febrile, tachycardic and weighed 45 kg for a height of 158 cm. He had neck stiffness and positive Brzezinski and Kerning signs. Q1. Which of the following should be ordered in the initial evaluation? A. Complete blood count B. Serum C-reactive protein C. Cytology, smear and culture of cerebrospinal fluid D. Administration of empirical antibiotics prior to any sampling procedure E. All of the above Answer:  The correct answer is E. Our patient had a leukocytosis of 13,800/μL with predominant neutrophils 9700/μL, Hemoglobin was 12.5  g/dL and the platelet count was 230,000 per microliter. Serum CRP was 9.8 mg/dL. Lumbar puncture brings back a fluid of cloudy appearance and examination of the cerebrospinal fluid yields 4.8 grams of protein per liter (reference range: 0.1–0.4). Glucose of CSF was only 15 mg/dL C. D. Cossou-gbeto (*) Internal Medicine, Hematology and Oncology Department – Aix-en-Provence Hospital Center, Aix-en-Provence, France e-mail: [email protected] L. Dangou Pediatric Departement, Bethesda Hospital, Cotonou, Benin M. G. Hounkpe ENT Department, University Hospital Hubert Koutoucou Maga of Cotonou, Cotonou, Benin J. Fortunato Pediatric Department, Goho Hospital Center of Abomey, Abomey, Bénin © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_114

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(reference range: 45–70), while simultaneous serum glucose at 98  mg/dL.  CSF culture was positive for Neisseria meningitidis. Q2. Which of the following evaluations is indicated in the next step? A. Electrophoresis of serum proteins B. Imaging of the skull C. Exploration of the complement system activity D. All of the above Answers:  The correct answer is D. Q3. Based on the identified germ (Neisseria meningitidis), what is the most likely diagnosis? A. HIV infection B. Complement deficiencies in C2, C3 C. Complement deficiencies in C5, C6, C7, C8, C9 D. Agammaglobulinemia E. IgG subclass deficiency Answers:  The correct answer is C. The repeated occurrence of bacterial meningitis may be associated with immunodeficiency. Terminal pathway components, i.e. C5-C9, and properdin deficiencies predispose to encapsulated extracellular bacteria, mainly Neisseria infections, and mannose-binding lectin (MBL) deficits are associated with a broad spectrum of microorganisms [1, 2]. The sinus scan did not show any communication between leptomeningeal compartments and sinus. The results of the explorations are summarized in Table 13.3. Antibody production to protein and non-protein antigens were normal. Q4. All of the following statements are true regarding the complement system, except A. The alternative complement system activation does not lead to direct bactericidal activity B. Products of the coagulation cascades can activate the complement system C. Products of cleavage of C3 and C1 components have a role in hypersensitivity D. Factor D is the only complement component that can be lost is substantial amounts in urine Answer:  The correct answer is C. The complement system consists of a set of more than thirty proteins that play a role in bacterial immunity, systemic inflammation, hypersensitivity and coagulation. The complement system has three activation pathways: the classical pathway, the mannoses pathway, and the alternate pathway (Fig. 114.1). Complement deficits can be hereditary or acquired. Acquired complement deficiencies are due to excessive consumption, as in systemic lupus erythematosus (SLE), decreased hepatic production, and less commonly loss in urine in severe chronic kidney disease or presence of auto-antibodies. Primary assay for detection of complement deficiencies should entail CH50, AP50, C3 and C4 which makes it possible to detect the main categories of complement deficits. Figure 114.2

114  Fever, Headache and Photophobia CLASSICAL PATHWAY Immune complex Other no immune activator C1-inhibitor

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MANNOSES PATHWAY Mannoses of pathogen

ALTERNATIVE PATHWAY Spontaneous activation Bacteria area

MBL MASP1 MASP2

C3 Facteur B Facteur D

C1q, C1r, C1s C4 C2

Factor I CR1 CD46 C4bp

C3 classic convertase C4b2a C3

CD 55

C3 convertase alternates C3bBb C3

C3b

C3b

C5 classic convertase C4b2a, C3b

CD 55

COMMON FINAL PATHWAY

Factor H Factor I CD 46 Factor H CR 1

C5 convertase alternates C3bBb, C3b

C5 C6 C7 C8 C9

CD 59

C5b9

Fig. 114.1  The complement system: activation and regulation pathways. MBL: mannose binding-­ lectin, MASP: mannose-associated serine protease

CH50 L, AP50 L, C3 L, C4 N C3 deficiency, factor H deficiency or factor I deficiency CH50 L, AP50 L, C3 N, C4 N Deficiency in fraction of the terminal: C5, C6, C7, C8

Bacterial infection

CH50 L, AP50N, C3 N, C4 N Early protein deficit of the classical pathway : C2, C1q, C1r, C1s (and C4 if C4 L)

CH50, Ap50, C3, C4

CH50 N, AP50 N, C3N, C4N Normal results, stop the exploration of the complement

CH50 N, AP50 L, C3 N, C4 N Properdin deficiency, Factor D deficiency or factor B

Fig. 114.2  Necessary explorations of the complement system during a bacterial infection. N: Normal level; L: Low level

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illustrates our diagnostic scheme. For the patient described above we found diminished activity of CH50 and AP50 with C4 and C3 fractions being normal. A fraction deficit in one of the components of common terminal pathway; C5, C6, C7, C8, or C9 is hence suspected. Q5. True or False: We must look for a deficit in C6 among other members of the family A. True B. False Answer:  The statement is true. Q6. True or False: Routine injections of the missing complement factor is the main therapeutic option for this patient A. True B. False Answer:  The statement is false. In contrast to humoral/immunoglobulin deficiencies, a deficiency in one component of the complement cannot be corrected in the long term by injections of missing proteins as their half-life is too short (generally less than a day). Currently, there is no specific treatment for complement deficiencies. Management of patients with these patients is hence based on prevention of infections and their appropriate treatment when they occur [3].

Practical Points • The complement system has three activation pathways: the classical pathway, the mannose pathway, and the alternate pathway • Repeated occurrence of bacterial meningitis is associated with deficiency of common terminal pathway components: C5-C9, and properdin • Mannose-binding lectin deficits are associated with a broad spectrum of microorganisms • Plasma half-life of most complement products is short, preventing effective infectious prevention by replacement therapy • Acquired complement deficiencies can appear due to excessive consumption, as in systemic lupus erythematosus (SLE), decreased hepatic production, and less commonly loss in urine in severe chronic kidney disease or presence of auto-antibodies • Primary assay for detection of complement deficiencies should entail CH50, AP50, C3 and C4 measurement

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References 1. Tebruegge M, Curtis N. Epidemiology, etiology, pathogenesis, and diagnosis of recurrent bacterial meningitis. Clin Microbiol Rev. 2008;21(3):519–37. 2. Rameix-Welti M-A, Chedani H, Blouin J, Alonso J-M, Fridman W-H, Fremeaux-Bacchi V. Infection par Neisseria meningitidis. Presse Méd. 2005;34(6):425–30. 3. Immune Deficiency Foundation. Complement deficiencies. In: Patient & family handbook for primary immunodeficiency diseases. 5th ed. USA: Immune Deficiency Foundation; 2015.

Chapter 115

Recurrent Meningitis Ibtihal Benhsaien, Ahmed Aziz Bousfiha, and Fatima Ailal

An 11-year-old girl from non-consanguineous parents was admitted to our hospital for a purpura fulminans. Her past medical history was positive for bacterial meningitis that had led to her admission at 18 months of age. Her family history was relevant for a sister with recurrent ear-nose-throat infections and bacterial meningitis at the age of 9 years old. She was admitted to the intensive care unit and immediately received intravascular fluid. Ceftriaxone 100  mg/kg/day and gentamycin 3  mg/kg/day were started empirically along with one dose of dexamethasone to reduce neurological sequel. The CBC showed: Hb 10.3  g/dL, leukocyte count: 13,154 /μL, neutrophils: 10,845 /μL, lymphocytes: 1783 /μL, platelets: 140,000 /μL, and serum CRP was 25.4  mg/dL (reference range  2.2  mmol/L). Total number of leukocytes and their subpopulations count in peripheral blood were within reference values. Unfortunately, our patients succumbed to death due to necrotizing colitis, peritonitis, brain edema and a residual defect of the lower edge of the interventricular septum patch. Q3. Which of the methods of genetic diagnosis is of choice in verifying DiGeorge syndrome? A. Multiplex polymerase chain reaction B. Western Blot C. Fluorescence in-situ hybridization D. Next genome sequencing Answer:  The correct answer is A. Multiplex PCR with oligonucleotide probe ligation (multiplex ligation PCR amplification: MLPA) is the most sensitive and specific method to detect intrachromosomal micro-reconstructions such as microdeletions and microduplications [2]. Up to 50 sequences obtained from a single DNA sample can be analyzed at a time using MLPA and only 20 ng of DNA is sufficient for analysis. It is also possible to use partially degraded samples and the high performance protocol yields specialist-­independent results as early as 24 hours. With MLPA becoming more and more affordable, it has now become a method of choice in diagnosis of DiGeorge syndrome [2, 3]. In order to perform postmortem molecular genetic verification of clinical diagnosis a dry sample of the boy’s blood from his newborn screening was requested from the archives of the “laboratory of Neonatal Screening Clinical and Diagnostic Center “Mother’s Health and Child” for DNA extraction and genetic analysis. The conducted studies confirmed deletion in the critical region at chromosome 22, del22q11.2 (region LCR22-A) [4, 5].

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To conclude, phenotypic manifestations of the boy were thymic hypoplasia, hypogammaglobulinemia, congenital heart disease, defective repair after surgery, repeated acute respiratory infections and pneumonia, and intestinal infection complicated by peritonitis, which led to a lethal outcome in 8.5 months. Let us move on to describe phenotype of the 2nd child of the family and the mother. Second child was a girl, was delivered by caesarean at 34  weeks following a pregnancy associated with preeclampsia. Her birth weight was 2190 grams, height was 43 cm and she was on respiratory support, which lasted for the first 3 months of life. In addition to congenital heart disease in form of arterial septal aneurysm, tricuspid insufficiency of the third degree, the girl showed thymus hypoplasia and hypogammaglobulinemia. Serum levels of calcium and number of lymphocytes in the peripheral blood corresponded to physiological values. She had dysplastic facial features including hypertelorism, submandibulism, and dolichocephaly. The girl suffered mild episodes of rhinorrhea during first months of life and an episode of viral respiratory infection at 1, 5  years old. A genetic study was conducted, during which a deletion of the critical section 22q11.2 was also revealed. Thus, the phenotypic manifestations of the girl were: thymic hypoplasia, hypogammaglobulinemia, congenital heart disease, mild respiratory infections, dysplastic facial features, dolichocephaly. Presence of two children with the same genetic syndrome within the same family, with different phenotypic manifestations, a genetic study of the mother was scheduled. Her mother, currently 35 years old remembers suffering from several episodes of pneumonia since 10 years old. She has also had arterial hypertension since 20 years old. Her mother phenotypically differs in dysplastic facial features with hypertelorism, pear-shaped nose and short neck. She also reports delays in sexual development as her menarche and signs of fertility appeared in 16 years of age. In laboratory data her peripheral blood cells count were within the reference limits and normal immunoglobulins levels with mildly increased IgA above the normative values. Ultrasound investigation of the thymus revealed 2 solid cysts and abdominal ultrasound of the abdominal cavity revealed steatosis of the liver. Q4. True or False: Genetic study warranted in patient’s mother although she is asymptomatic A. True B. False Answer:  The correct answer is A. When genetic study was carried out [6], a deletion identical to the deletion in the daughter and son, was identified and she was diagnosed with the DiGeorge syndrome. Thus, the phenotypic manifestations of the mother can be summarized as dysplastic facial features and repeated pneumonia in childhood, delayed sexual ­development in adolescence, presence of solid cysts in the thymus and steatosis of the liver. This case occurred without the characteristic phenotypic manifestations

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peculiar to DiGeorge syndrome or any congenital malformations in heart or parathyroid glands, and significant acute infectious episodes were observed only in childhood [7–9]. In the sample of father’s DNA, 36-year-old, no microstructural disturbances of this region were detected. All indicators of the physical condition were within the norm although he has some dysplastic features of the facial skeleton. Q5. Which of the following recommendations is most appropriate for the patient’s parents in possible subsequent pregnancies? A. Genetic studies as the time of delivery B. Prenatal diagnosis C. Amniocentesis in 15 weeks of gestation D. Chorionic Villous Sampling (CVS) at 12 weeks of gestation Answer:  The correct answer is C. Pregnancy planning should be supervised by a geneticist and intrauterine diagnostics to exclude or detect a genetic defect in the fetus should be carried out. Amniocentesis is the first diagnostic choice for cytogenetic and molecular analyses of the fetus. DNA extracted from the amniotic fluid is analyzed by MLPA or fluorescence in situ hybridization (FISH) [10]. Practical Points • DiGeorge syndrome is caused by a small deletion in chromosome 22 • Multiplex PCR with oligonucleotide probe ligation is a gold standard method for diagnosis of DiGeorge syndrome • Leukopenia, low CD3+ cells count, low serum calcium, arterial trunk and ventricular septal defect, and hypoplasia of the thymus should direct toward a diagnosis of DiGeorge syndrome

References 1. Tuzankina IA, Deryabina SS, Vlasova EV, Bolkov MA. Familial case of chromosome 22q11.2 deletion syndrome. Med Immunol (Russia). 2017;19(1):95–100. (In Russ.). https://doi. org/10.15789/1563-0625-2017-1-95-100. 2. Deriabina SS, Karakina ML, Tuzankina IA.  MLPA method in identifying a family case of chromosome 22 deletion syndrome. Bull Ural Med Acad Sci. 2014;3(49):206–8. 3. Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 deletion syndrome. Am J Med Genet A. 2005;138(4):307–13. 4. Fung WL, Butcher NJ, Costain G, Andrade DM, Boot E, Chow EW, Chung B, Cytrynbaum C, Faghfoury H, Fishman L, Garcia-Minaur S, George S, Lang AE, Repetto G, Shugar A, Silversides C, Swillen A, van Amelsvoort T, McDonald-McGinn DM, Bassett AS. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med. 2015;17(8):599–609. 5. De Decker R, Bruwer Z, Hendricks L, Schoeman M, Schutte G, Lawrenson J. Predicted v. real prevalence of the 22q11.2 deletion syndrome in children with congenital heart disease present-

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ing to Red Cross War Memorial Children’s Hospital, South Africa: a prospective study. S Afr Med J = Suid-Afrikaanse tydskrif vir geneeskunde. 2016;106(6 Suppl 1):S82–6. 6. Schwinger E, Devriendt K, Rauch A, Philip N. Clinical utility gene card for: DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome, chromosome 22q11.2 deletion syndrome (22q11.2, TBX1). Eur J Hum Genet. 2010;18(9). 7. Maggadottir SM, Sullivan KE. The diverse clinical features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). J Allergy Clin Immunol Pract. 2013;1(6):589–94. 8. Davies EG.  Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia. Front Immunol. 2013;4:322. 9. Kobayashi D, Sallaam S, Humes RA. Tetralogy of Fallot with complete DiGeorge syndrome: report of a case and a review of the literature. Congenit Heart Dis. 2013;8(4):E119–26. 10. Hacihamdioglu B, Hacihamdioglu D, Delil K. 22q11 deletion syndrome: current perspective. Appl Clin Genet. 2015;8:123–32.

Chapter 128

Erythrodermic Rash and Seizures Andrew R. Gennery

A 2-month-old boy, the product of a non-consanguineous relationship, presented at 5 weeks of age with seizures due to profound hypocalcaemia and required intubation. Three older siblings were well, and there was a history of maternal childhood seizures. He was noted to be anaemic and received two cytomegalovirus negative packed red blood cell transfusions. Three weeks later, he developed a widespread, generalized thickened exfoliating erythematous rash, associated with evolving alopecia involving the eyebrows. Clinical examination also revealed hepatosplenomegaly with widespread cervical, axillary and inguinal lymphadenopathy. Laboratory investigations revealed: Hb 7.9 g/dL, platelet: 536/μL, WBC: 23.78/μL with neutrophils 5.95/μL, lymphocytes: 12.37/μL, and eosinophils 3.57/μL.  Ionized calcium was 9  mg/dL, while parathyroid hormone was 188.6  pg/dL (reference range: 1131.6–5469.4  pg/dL). Cytogenetic analysis failed to induce metaphase, thereby yielded no results. Rhinovirus was detected on nasopharyngeal secretions but no other evidence of infection was apparent. Immunological investigations revealed the following: CD3+: 12,418/μL (reference: 2300–7000), CD4+: 11,754/μL (reference: 1400–5300), CD8+: 485/μL (reference: 400–2200), CD19+: 1050/μL (reference: 600–3000), CD16+/CD56+: 1604/μL (reference: 100–1400), and 92% of activated DR+ T cells. Analysis of the variable portion of β subunit of T cell receptor showed marked oligoclonal expansion of few families in which Vβ families was represented. T lymphocytes failed to proliferate when stimulated with phytohemagglutinin. Finally, serum IgM and IgA were absent, and IgG was at the lowest end of normal range and serum IgE was 944 IU/mL (0–15).

A. R. Gennery (*) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Great North Children’s Hospital, Newcastle upon Tyne, UK e-mail: [email protected] © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_128

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Q1. What is the best initial diagnostic test in this patient? A. Detailed T-lymphocyte enumeration and serum calcium level B. Radioallergosorbent tests against food allergens and house dust mite C. Array comparative genomic hybridization or fluorescent in situ hybridization D. Evaluation of natural killer cell cytotoxic function E. Measurement of T cell receptor excision circles Answer:  The correct answer is C. The patient has chromosome 22q11 deletion, also known as DiGeorge syndrome or velocardiofacial syndrome, a common genetic disorder affecting approximately 1:4000 births, which can affect cardiovascular, parathyroid and thymic development [1]. Defects in the development of the pharyngeal arches and pouches, which form the common embryonic precursor of the conotruncal regions of the heart, parathyroid glands and thymus is the primary event in DiGeorge syndrome. This results from impaired neural crest cell migration into pouch ectoderm. Evolution of thymic mesenchyme is dependent on migration of neural crest cells from pharyngeal arch, which then promote thymic epithelium development. Thymic epithelial differentiation later becomes independent of mesenchymal cells, once the thymic organelle is able to support immature thymocytes migrating from bone marrow-derived precursors. Cellular cross-talk between developing lymphoid and thymic epithelial cells is critical for further thymic development [2]. Severely atrophic thymus with a failure in corticomedullary demarcation is the consequence of defects in any gene that promotes T-lymphocyte development, as happens with most severe combined immunodeficiencies (SCID) [3]. Three major immunological patterns can occur in 22q11 deletion syndrome: 1. The most severe clinical scenario: complete absence of the thymus, a lymphocytosis and SCID-like phenotype. This is a rare condition and affects fewer than 1% of patients with 22q11 deletion [4]. Associated with this phenotype, and even rarer is an Omenn syndrome-like clinical presentation [5]. 2. The most frequent clinical scenario: patients have small, atrophic, thymus with low T cell count. They present with recurrent sinopulmonary infections in early childhood, which resolves by adolescence. 3. An increasingly recognized clinical complication: 22q11 deletion associated with autoimmunity, most commonly affecting thyroid function [6, 7]. Diagnosis of 22q11 deletion syndrome is performed by one of the following methods: first, array comparative genomic hybridization which is the preferred and most appropriate investigation to detect 22q11 deletion. This has superseded fluorescent in situ hybridization (FISH), which may not detect smaller deletions. Secondly, if array comparative genomic hybridization is not available, a FISH study for the 22q11.2 deletion along with a karyotype should be requested. Nonetheless, chromosome metaphases for karyotyping are induced by stimulating cells with phytohemagglutinin, and in patients with complete athymic 22q11 deletion, a karyotype request may

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not yield any result as there are no T lymphocytes to proliferate. Severe hypocalcaemia, as in this case, is likely to be associated with poor T-lymphocyte function [8]. Q2. All of the following options can explain the abnormal T-lymphocyte phenotype observed in this patient, except A. An aberrant response to an allergen leading to the raised IgE and eosinophilia B. Transfusion-related graft versus host disease due to transfusion of non-­irradiated red blood cells C. Materno-fetal graft versus host disease D. Omenn syndrome-like phenotype due to oligoclonal expansion of autoreactive autologous T lymphocytes Answer:  The correct answer is A. The clinical presentation of exfoliative erythroderma and evolving alopecia, in association with lymphadenopathy and hepatosplenomegaly is consistent with congenital reticuloendotheliosis with eosinophilia, or Omenn syndrome. The escape of a few, poorly tolerized autoreactive T lymphocytes leads to exuberant oligoclonal expansion, with evidence of autoimmunity, particularly in the skin, but possibly also in lungs, liver or gut. T lymphocytes are ineffective in clearing infection, and therefore co-existent infection might complicate the autoimmunity phenotype. Importantly, viral infections in respiratory or gastrointestinal tracts, induced by live vaccines or opportunistic infection such as Pneumocystis jirovecii pneumonitis, can mimic autoimmune features in histology [9]. Engraftment of transplacentally acquired maternal T lymphocytes can cause a similar clinical picture, although usually less severe than that observed due to autologous T-lymphocyte expansion [10]. Transfusion-related graft versus host disease (GVHD) is also common in severely immunocompromised patients, including those with severe T-lymphocyte defects [11]. Therefore, all infants with severe immunodeficiency, suspected or confirmed, are warranted to receive irradiated blood transfusion products in order to prevent infusion of competent alloreactive T lymphocytes. Maternal engrafment and transfusion-related GVHD can only be distinguished by identifying origin of the T lymphocytes in the patient, and curiously by karyotyping (i.e. XY/XX FISH analysis) in the case of sex mismatch. Other potential causes of erythroderma in the infant are listed in Table 128.1.

Table 128.1  Causes of Erythroderma in the Infant associated with Immunodeficiency Disease Omenn syndrome Materno-foetal graft versus host disease Transfusion-related graft versus host disease Comel-Netherton Syndrome

Cause ‘leaky’ form of severe combined immunodeficiency Maternal T lymphocyte engraftment in patient with severe combined immunodeficiency Blood transfusion donor T lymphocyte engraftment in patient with severe combined immunodeficiency Mutation in SPINK5

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Q3. Which one is the most effective treatment approach for a patient with athymic 22q11 deletion syndrome? A. There is no treatment and palliative care should be offered B. A haploidentical T lymphocyte depleted stem cell transplant preceded by myeoablative chemotherapy conditioning C. Anti-viral prophylaxis D. Thymic transplantation E. HLA-identical sibling stem cell infusion Answer:  The correct answer is D. In conventional severe combined immunodeficiency, the genetic defect prevents maturation of T-lymphocyte development. In athymic 22q11 deletion syndrome, lack of T lymphocytes is due to absence of thymic matrix to support T-lymphocyte development while thymic precursors develop normally. A myeloablative stem-cell transplant procedure will not repair the thymic matrix, while T-lymphocyte development can proceed normally in the presence of normal thymic tissue. A stem-cell transplant procedure is most successful when an HLA-identical sibling donor is used, but even in this situation, the risk of GVHD is high [12]. Chemotherapy preconditioning is not required for the reasons outlined above and donor stem-cells will not be able to develop into T lymphocytes in the absence of a functional thymus. T-lymphocyte repertoire delivered by such procedure will be limited, and pose a risk of immune exhaustion, development of autoimmunity and or lymphoid malignancies in long notice. Transplantation of thymic tissue is a specialized procedure, still currently available in only two centers worldwide. Slices of thymus, usually harvested from tissue discarded during the course of pediatric cardio-thoracic surgery, are cultured to remove T lymphocytes and thymocytes, and implanted, usually in the thigh, in the patient. If successful, the thymic precursors from the patient’s bone marrow populate the thymic scaffold and develop cellular immunity [13, 14]. In a patient like the one described above, it may be necessary to remove the autoreactive T-lymphocyte using anti-thymocyte immunoglobulin, prior to insertion of the thymic slices. Whilst many patients develop some T-lymphocyte immunity, they remain relatively T lymphocytopenic, and there is a high incidence of future autoimmunities [14].

Practical Points • The 22q11 deletion syndrome, also known as DiGeorge syndrome or velocardiofacial syndrome is a result of defect in embryogenic development of the parathyroid, conotruncal region of the heart and the thymus • In the most severe form DiGeorge syndrome is characterized by complete absence of the thymus, a lymphocytosis and SCID-like phenotype • Diagnosis of 22q11 deletion syndrome is now performed by array comparative genomic hybridization which is the preferred and most appropriate investigation to detect 22q11 deletion which has substituted fluorescent in situ hybridization

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References 1. Gennery AR.  Immunological aspects of 22q11.2 deletion syndrome. Cell Mol Life Sci. 2012;69(1):17–27. 2. van Ewijk W, Shores EW, Singer A.  Crosstalk in the mouse thymus. Immunol Today. 1994;15(5):214–7. 3. Poliani PL, Facchetti F, Ravanini M, Gennery AR, Villa A, Roifman CM, Notarangelo LD.  Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome. Blood. 2009;114(1):105–8. 4. Ryan AK, Goodship JA, Wilson DI, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond FL, Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B, Novelli G, Hurst JA, Ignatius J, Green AJ, Winter RM, Brueton L, Brondum-Nielsen K, Scambler PJ, et al. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997;34(10):798–804. 5. Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J Allergy Clin Immunol. 2004;113(4):734–41. 6. McLean-Tooke A, Spickett GP, Gennery AR. Immunodeficiency and autoimmunity in 22q11.2 deletion syndrome. Scand J Immunol. 2007;66(1):1–7. 7. Tison BE, Nicholas SK, Abramson SL, Hanson IC, Paul ME, Seeborg FO, Shearer WT, Perez MD, Noroski LM, Chinen J. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. 2011;128(5):1115–7.e1-3. 8. Herwadkar A, Gennery AR, Moran AS, Haeney MR, Arkwright PD.  Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome. J Clin Pathol. 2010;63(2):151–5. 9. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008;122(6):1082–6. 10. Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz K, Friedrich W.  Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients. Blood. 2001;98(6):1847–51. 11. Sebnem Kilic S, Kavurt S, Balaban Adim S. Transfusion-associated graft-versus-host disease in severe combined immunodeficiency. J Investig Allergol Clin Immunol. 2010;20(2):153–6. 12. Janda A, Sedlacek P, Honig M, Friedrich W, Champagne M, Matsumoto T, Fischer A, Neven B, Contet A, Bensoussan D, Bordigoni P, Loeb D, Savage W, Jabado N, Bonilla FA, Slatter MA, Davies EG, Gennery AR.  Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly. Blood. 2010;116(13):2229–36. 13. Li B, Li J, Devlin BH, Markert ML. Thymic microenvironment reconstitution after postnatal human thymus transplantation. Clin Immunol. 2011;140(3):244–59. 14. Davies EG, Cheung M, Gilmour K, Maimaris J, Curry J, Furmanski A, Sebire N, Halliday N, Mengrelis K, Adams S, Bernatoniene J, Bremner R, Browning M, Devlin B, Erichsen HC, Gaspar HB, Hutchison L, Ip W, Ifversen M, Leahy TR, McCarthy E, Moshous D, Neuling K, Pac M, Papadopol A, Parsley KL, Poliani L, Ricciardelli I, Sansom DM, Voor T, Worth A, Crompton T, Markert ML, Thrasher AJ. Thymus transplantation for complete DiGeorge syndrome: European experience. J Allergy Clin Immunol. 2017;140(6):1660–70.e16.

Chapter 129

Bloody Diarrhea Rakesh Kumar Pilania, Rashmi Rekhi, and Deepti Suri

A 9-month-old, boy, second in birth order presented with acute-onset fever, cough and respiratory distress. He had been unwell for the past 6 months with recurrent episodes of blood-stained diarrheal stools. He was exclusively breastfeed till 6  months of age and had not responded to cow’s milk exclusion diet. His elder brother had similar illness with bloody diarrhea and atopic dermatitis and had succumbed to pneumonia at 1 year of age. The mother had also lost her brother in early childhood. On examination, he was tachypneic had bilateral crepitation and hepatosplenomegaly. Macular erythematous lesions with scaling compatible with atopic dermatitis, were noted on trunk, face and scalp (Fig.  129.1). Laboratory results revealed anemia, leukocytosis with microthrombocytopenia and raised ESR. Serum immunoglobulin profile was within normal range. Q1. Which of the following tests will help confirm the diagnosis in this patient? A. Wiskott-Aldrich syndrome protein/WASp expression and WAS gene analysis B. Functional antibodies assessment C. T and B cell immunophenotyping by flow cytometry D. Phagocytic assay with nitroblue tetrazolium test Answer:  The correct answer is A. Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized by a triad of eczema, thrombocytopenia, and immunodeficiency and caused by mutation in the WAS gene. It has varied clinical presentations ranging from intermittent/persistent thrombocytopenia as in X-linked thrombocytopenia (XLT) to lethal classical WAS [1]. Bleeding is the most common symptom seen throughout the spectrum of WAS, mostly in form of petechiae and ecchymosis. R. K. Pilania · R. Rekhi · D. Suri (*) Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_129

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Fig. 129.1  Eczematous rash on scalp (a) and on trunk (b) in a child with Wiskott Aldrich syndrome

Many patients however, present with severe bleeding episodes as hematemesis and melena. Bloody diarrhea in newborns and infants should always rise suspicion for WAS. Polysaccharide-coated bacteria pose a special risk in these patients because of the impaired capacity to produce antibodies of the IgG2 subclass against polysaccharide antigens. Opportunistic infections such as Pneumocystis jirovecii have also been reported and tend to increase during follow-up and are seldom seen in the early months of life [2, 3]. Eczema usually appears early in life and is refractory to usual management for atopic dermatitis. Microthrombocytopenia is an important clinical clue to the diagnosis. The quantification of intracytoplasmic WASp expression serves as a rapid and inexpensive screening test for WAS [3], while normal WASp expression may not rule out the disease. Molecular sequencing of WAS gene located on the short arm of the X chromosome at Xp11.22–p11.23 is confirmatory [4, 5]. A clinical score has been proposed and validated for classification of patients from XLT to WAS (Table 129.1). A score of 1-2 identifies patients affected with a milder form of the disease, i.e. XLT, while score of 3-5 suggests the severe variant or classical WAS. Score 5 is assigned to patients developing autoimmunity or malignancy [5, 6]. Q2. Genetic testing of the index patient confirmed a mutation in WAS gene and the mother was found to be a carrier. What is the risk of the disease transmission in subsequent pregnancies? A. 50% of boys are affected B. 100% boys affected C. 100% girls affected D. 50% of girls are carriers E. Answers A and D are correct Answer:  The correct answer is E.

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Table 129.1  Wiskott-Aldrich severity classification scoring system Clinical score Thrombocytopenia Small platelets Eczema Immunodeficiency Infections Autoimmunity or malignancy

iXLT  A), which results in a frameshift with a premature stop codon at amino acid 190. X-linked thrombocytopenia (XLT) represents an allelic variant caused by loss-­of-­ function mutations in the WAS gene. Other allelic variants associated with mutations in this gene include typical Wiskott-Aldrich syndrome (WAS) with complete lossof-function of the gene, X-linked neutropenia (XLN), and X-linked myelodysplasia (XL-MDS), the last two being caused by gain-of-function mutations in WAS [1, 2]. WAS is an X-linked disorder classically characterized by increased susceptibility to infections with a combined immunodeficiency phenotype, thrombocytopenia, and eczema. XLT is associated with a milder form characterized by congenital thrombocytopenia and mild eczema. WAS and XLT are also associated with autoimmune disease in 40–70% of cases [3], and malignancy in 10–20% of cases [3]. In particular, WAS and XLT have been associated with IgA nephropathy and renal disease requiring transplantation [4]. In all phenotypes related to WAS mutation there is a variable degree of impact on lymphocyte function. A clinical scoring system (0–5) has been developed for prognosis and classification of WAS [5]. Patients with gainof-function mutations in WAS (XLN and/or XL-MDS) have WAS scores of 0 (lowest score). Importantly, transition from a low to high score is possible over time. Our patient has a history of congenital thrombocytopenia, childhood eczema, bloody diarrhea, and IgA-associated renal failure requiring transplantation. This is most consistent with XLT, the milder form/subtype of WAS (Table 131.1). Q2. Which one of the following findings is least likely is a patients with WAS? A. Thrombocytopenia B. Large platelets with decreased granules C. Normal natural killer cell numbers but decreased NK cytotoxicity D. Impaired T cell activation and migration Answer:  The correct answer is B. Table 131.1  Comparing typical Wiskott-Aldrich syndrome (WAS) with X-linked thrombocy­ topenia (XLT) and X-linked neutropenia (XLN) Typical WAS Complete loss of function Increased susceptibility + to infections Thrombocytopenia/ +/small platelet size platelets Increased risk of + autoimmune disease Increased risk of + malignancy

WAS gene mutation

XLT Variable phenotypic effect, but milder than typical WAS −

X-linked neutropenia Gain of function mutation. Also associated with X-linked myelodysplasia −

+/small platelets

−

+

−

+

−

+ and – indicate presence or absence of a sign

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One major clinical feature of WAS and XLT is small platelets that are decreased in number and size. XLT and WAS are both associated with an increased risk of infections and diverse clinical presentations. In WAS, immunologic abnormalities can include impaired T cell activation and migration, which occurs in approximately 50% of patients [3]. NK cell numbers are typically normal but there is decreased spontaneous NK cytotoxicity [6]. There can also be abnormal immunoglobulin levels, most notably low/normal IgG and IgM and high IgE and/or IgA [7]. Patients with WAS depict impaired response to vaccines as well, though this data is variable and not uniformly seen in all WAS-related phenotypes [3, 8]. Q3. What is the next best step to confirm the diagnosis? A. Lymphocyte subset quantitation B. Measure antibody response to vaccination C. WAS protein flow cytometry and genetic testing D. NK cell cytotoxicity Answer:  The correct answer is C. Confirmatory testing for WAS or XLT includes WAS protein (WASp) flow cytometry, and genetic analysis of the WAS gene for mutations. Sequence analysis of the WAS gene is useful for genotype-phenotype correlation, and facilitates accurate classification, and determination of the patients prognosis [9]. While small platelet size, poor vaccine response, and abnormal T and B cell subsets can all be seen in both WAS and XLT, genetic testing of the WAS gene is needed to confirm the diagnosis, and enable phenotypic correlation. Q4. What is the main role of WASp in the immune system? A. Actin cytoskeleton remodeling B. T cell receptor co-factor C. Regulation of differentiation of neural crest cells D. Acts as a transcription activator after phosphorylated by Janus kinases Answer:  The correct answer is A. WASp plays a critical role in actin cytoskeleton remodeling, affecting cell movement and morphology [1, 10]. WASp expression is usually absent in classical WAS, and low in the less severe phenotype, XLT [11]. WASp is involved in transducing signals from the cell surface to the actin cytoskeleton. Absent or defective WASp can result in cytoskeletal defects that compromises cell proliferation, phagocytosis, immune synapse formation, cell adhesion and directed migration [10]. This further impairs T cells and antigen presenting cells interaction, resulting in impaired T cell activation as well as abnormal spontaneous NK cell cytotoxic function. Finally, impaired T cell function can also alter B cell activation, resulting in a reduction in circulating mature B cells [12]. Q5. What is the treatment of choice for classical WAS? A. Prophylactic antibiotics B. Intravenous immunoglobulin

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C. Vaccination again encapsulated organisms D. Hematopoietic stem-cell transplant Answer:  The correct answer is D. For patients with classical WAS, HLA-matched hematopoietic stem cell transplantation (HSCT) is the treatment of choice. HSCT is a curative treatment for WAS, and the current standard-of-care for patients with both WAS and XLT. The overall survival rate is 80–90% in patients with HLA-matched donors [13]. While XLT has a milder phenotype and improved survival compared to classical WAS, event-free survival is significantly affected by conservative treatment [14], which includes prophylactic antibiotics intravenous immunoglobulin, immunosuppression therapy, especially for autoimmune cytopenias, and even splenectomy. Choice of HSCT for XLT is more variable and depends on the individual case and disease burden. The overall survival for HSCT in XLT is 83% in a recent study [14]. The decision to transplant in XLT also depends on the specific genetic defect in the WAS gene, for example the intronic splice-variant in this patient is associated with a higher risk of lymphoma [9]. Finally, gene therapy is also currently being investigated for the treatment of WAS and XLT [15]. Immunoglobulin replacement is recommended for all WAS/ XLT patients who undergo splenectomy.

Practical Points • Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by increased susceptibility to infection, combined immunodeficiency, thrombocytopenia, and eczema • X-linked thrombocytopenia (XLT) is a milder form of the disease characterized by congenital thrombocytopenia and mild eczema • Immunodeficiency in WAS and XLT varies greatly, and abnormalities include impaired T cell function, decreased NK cytotoxicity, abnormal immunoglobulin levels, and impaired IgG2 response to polysaccharide vaccines • The confirmatory tests for WAS or XLT is through WAS protein flow cytometry and genetic analysis of the WAS gene for mutations • For patients with classical WAS, HLA-matched HSCT is the treatment of choice and is considered curative • Choice of HSCT for XLT is dependent on the individual case, specific genetic mutation, and disease burden • Emerging treatments include gene therapy

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References 1. Ancliff P, Blundell M, Cory G. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood. 2006;108(7):2182–9. 2. Massaad M, Ramesh N, Geha R. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285(1):26–43. 3. Sullivan K, Mullen C, Blaese R. A multi-institutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125(6):876–85. 4. Hoshino A, Shimizu M, Matsukura H, Sakaki-Nakatsubo H, Nomura K, Miyawaki TK.  Allogeneic bone marrow transplantation appears to ameliorate IgA nephropathy in a patient with X-linked thrombocytopenia. J Clin Immunol. 2014;34(1):53–7. 5. Imai K, Nonoyama S, Ochs HD. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol. 2003;3(6):427–36. 6. Orange J, Roy-Ghanta S, Mace E.  IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function. J Clin Invest. 2011;121(4):1535–48. 7. Ozcan E, Notarangelo L, Geha R. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol. 2008;122(6):1054–62. 8. Buchbinder D, Nugent D, Fillipovich A. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55–66. 9. Albert M, Bittner T, Nonoyama S.  X-linked thrombocytopenia (XLT) due to WAS mutations : clinical characteristics, long-term outcome, and treatment options. Blood. 2010;115(16):3231–8. 10. Blundell M, Worth A, Bouma G, Thrasher A. The Wiskott-Aldrich syndrome: the actin cytoskeleton and immune cell function. Dis Markers. 2010;29(3–4):157–75. 11. Thrasher A, Burns S.  WASP: a key immunological multitasker. Nat Rev Immunol. 2010;10(3):182–92. 12. Meyer-bahlburg A, Becker-herman S, Humblet-baron S.  Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis. Blood. 2015;112(10):4158–70. 13. Shin C, Kim M-O, Li D. Outcomes following hematopoietic cell transplantation for Wiskott– Aldrich syndrome. Bone Marrow Transplant. 2012;47(11):1428–35. 14. Oshima K, Imai K, Albert M, Bittner T, Strauss G, Filipovich A, Morio T, Kapoor N, Dalal J, Schultz K, Casper J, Notarangelo L, Ochs H.  Hematopoietic stem cell transplantation for X-linked thrombocytopenia with mutations in the WAS gene. J Clin Immunol. 2015;35(1):15–21. 15. Abina SH-B, Gaspar H, Blondeau J, Caccavelli L, Charrier S, Buckland K. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;31315:1550–63.

Chapter 132

Bloody Stool and Recurrent Infections Sevgi Köstel Bal and Figen Doğu

A 6-month-old boy presented to our clinic with bloody stool and recurrent upper respiratory tract infections. Born from a 21-year-old mother after an uncomplicated pregnancy, he is the first child of consanguineous parents with no family history of similar conditions. In his neonatal period blood was frequently observed in stool and family physician prescribed therapy for anal fissure but the bleeding persisted. At three months of age he was admitted to a local hospital with bloody stool where he was diagnosed with idiopathic thrombocytopenic purpura (ITP) and received intravenous immunoglobulin and steroids. Thrombocytopenia persisted regardless of the therapy and he experienced an episode of otitis media and pneumonia between 3 and 6  months of age. On his admission to clinic, mild eczema, petechia and hepatosplenomegaly were detected during the physical exam. Laboratory evaluation revealed hypochrome microcytic anemia and thrombocytopenia (Hb: 8.1  g/dL, MCV: 70  fL, RDW: 15.2, WBC: 8200/μL, platelet: 18,000,000/μL, MPV: 5.7 fL) and low IgM levels. His peripheral blood smear did not show any blasts. Q1. What is the most likely diagnosis? A. Chronic Idiopathic thrombocytopenic purpura B. Wiskott-Aldrich syndrome

S. K. Bal Ankara University School of Medicine, Department of Pediatric Allergy and Immunology, Ankara, Turkey F. Doğu (*) Ankara University School of Medicine, Department of Pediatric Immunology and Allergy, Ankara, Turkey © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_132

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C. Evans syndrome D. Leukemia Answer:  The correct answer is B. Wiskott-Aldrich syndrome (WAS) is a primary immune deficiency having an X-linked inheritance pattern and classically characterized by thrombocytopenia with small platelets, eczema and recurrent infections [1]. The disease is caused by mutations in the WAS gene coding the WAS protein (WASp) which is involved in cell signaling and cytoskeleton reorganization. Three different phenotype of the disease are described: Classic WAS, X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN), depending on the type and/or site of mutation and its effect on protein expression, albeit with some exceptions. Early manifestations of WAS and XLT consist of petechia, bruises and bloody diarrhea often present from neonatal period. Characteristic finding at diagnosis both in classic WAS and XLT is microthrombocytopenia. Infections including purulent otitis media are frequent during the first 6 month of life [2]. Because of the wide spectrum of the clinical presentation, WAS/XLT should be considered in every male presenting with bleeding associated with congenital or early-onset thrombocytopenia and small platelets. Evaluation of WASp expression by flow cytometry and screening the WAS gene by sequence analysis are warranted to confirm the diagnosis and assess the disease severity [3]. Mutations that cause decreased WASp levels result in XLT, whereas mutations that abolish WASp expression or result in the expression of a truncated protein are associated with WAS. The most common cause of acute onset of thrombocytopenia in an otherwise well child is ITP [4]. There is a history of a preceding viral infection 1–4 weeks before the onset of thrombocytopenia. Findings on physical examination are petechia and purpura and rarely splenomegaly, lymphadenopathy, bone pain, and pallor. Severe thrombocytopenia (platelet count 90% [6]. If a full-matched donor is present, HSCT is the first-line treatment. Mismatched donors and older patients are factors associated with higher mortality and morbidity. Recently, gene therapy has offered a therapeutic option for high-risk patients [7]. Practical Points • Mutations in the WAS gene can result in either of the three main phenotypes: classic Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia • WAS/XLT should be considered in every male presenting with bleeding associated with congenital or early-onset thrombocytopenia and small platelets

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References 1. Candotti F. Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J Clin Immunol. 2018;38(1):13–27. 2. Ochs HD, Smith CIE, Puck J. Primary immunodeficiency diseases: a molecular and genetic approach. 3rd ed. Oxford; New York: Oxford University Press; 2014. 3. Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26–43. 4. Kliegman R, Behrman RE, Nelson WE. Nelson textbook of pediatrics. 20th ed. Phialdelphia, PA: Elsevier; 2016. 5. Mantadakis E, Farmaki E. Natural history, pathogenesis, and treatment of Evans syndrome in children. J Pediatr Hematol Oncol. 2017;39(6):413–9. 6. Shin CR, Kim MO, Li D, Bleesing JJ, Harris R, Mehta P, Jodele S, Jordan MB, Marsh RA, Davies SM, Filipovich AH. Outcomes following hematopoietic cell transplantation for Wiskott-­ Aldrich syndrome. Bone Marrow Transplant. 2012;47(11):1428–35. 7. Ghosh S, Gaspar HB.  Gene therapy approaches to immunodeficiency. Hematol Oncol Clin North Am. 2017;31(5):823–34.

Chapter 133

Idiopathic Thrombocytopenic Purpura Maria Hatzistilianou, Marianna Janoudaki, Michel Massaad, Raif Geha, and Maria Kanariou

A 5-year-old boy was admitted to our unit for workup of his thrombocytopenia and bleeding from his right ear. In his past medical history he was diagnosed with “idiopathic thrombocytopenic purpura” at the age of 40 days with reported recurrent infections, nose bleeding, ear bleeding and hematochezia. His family history revealed no similar condition. Examination revealed petechiae and ecchymosis at the upper and lower limbs and oral mucosa, and eczema at his face with crusting from pruritus. Laboratory results revealed: IgM: 17 mg/dL, IgG: 917 mg/dL, IgA: 281 mg/dL, and total IgE: 402 IU/mL. His mother reported that he had received intravenous immunoglobulin 2 g/Kg for his thrombocytopenia 2 weeks ago. The immune phenotype in peripheral blood cells showed up CD3+ 47%, CD3+/CD4+ 22%, CD3+/CD8+ 14%, CD19+ 21% and CD3−/CD16+/ CD56+ 28%.

M. Hatzistilianou (*) 2nd Department of Pediatrics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece e-mail: [email protected] M. Janoudaki Department of Immunology and Histocompatibility, “Aghia Sophia” Children’s Hospital, Athens, Greece M. Massaad · R. Geha Division of Allergy/Immunology/Rheumatology/Dermatology, Children’s Hospital, Harvard Medical School, Boston, MA, USA M. Kanariou Department of Immunology-Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies, Paediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_133

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Q1. What is the most likely diagnosis? A. Wiskott-Aldrich syndrome B. Idiopathic thrombocytopenic purpura C. Hyper-IgM syndrome D. Severe combined immunodeficiency E. Acute lymphoblastic leukemia F. Human immunodeficiency infection Answer:  The correct answer is A. Wiskott-Aldrich syndrome (WAS) is a severe congenital primary immunodeficiency disorder characterized by the clinical triad of microthrombocytopenia, recurrent infections and eczema [1, 2]. The first clinical signs are petechiae and ecchymosis of the skin and oral mucosa and bloody diarrhea. Patients may have prolonged bleeding from the umbilical stump. With the loss of maternally transported IgG during 4–8 months of age, infants begin to develop infections. These are most commonly in form of otitis media, pneumonia, sepsis and meningitis are caused by polysaccharide-coated bacteria. Atopic symptoms and eczema are frequently present. Eczema ranges from mild to severe, and patients usually present earlier than immunocompetent infants. Milk and other food allergies are also associated with eczema in Wiskott-Aldrich syndrome. Eczema may worsen in the presence of infections as well as during the winter. Q2. What is the best confirmatory diagnostic test in this patient? A. Nitroblue tetrazolium and dihydrorhodamine test B. Fluorescent in situ hybridization C. Flow cytometry for WAS protein and genetic analysis of WAS gene D. CH50 assay E. Serum C3, C4, C2 levels Answer:  The correct answer is C. The WAS protein (WASp) is important in the structure and function of most blood cells. Decreased or absent WASP protein in blood cells strengthens the diagnosis. Flow cytometry showed a total absence or decrease of the WAS protein in T lymphocytes and other blood cells. The flowcytometry method is a quick and best suited method to differentiate WAS from other hematologic differential diagnoses [1, 2]. Q3. True or False: WASP is involved in relaying signals from the surface of blood cells to the actin cytoskeleton. A. True B. False Answer:  The correct answer is True. WASp signaling activates cells and triggers their movement and attachment to other cells and tissues. In WBCs, this signaling allows the actin cytoskeleton to establish the interaction between cells and the foreign invaders that they target in the

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so called “immune synapse”. Loss of WASp signaling disrupts the function of the actin cytoskeleton in developing blood cells [3, 4]. Similarly, a lack of functional WASP in platelets impairs their development, leading to reduced size and early cell death manifested by thrombocytopenia [3, 4]. Q4. What is the most appropriate treatment in this patient? A. Hematopoietic stem-cell transplantation and gene therapy B. Avoid any prophylactic medication C. Treatment with steroids for all his life D. Immunosuppressed drugs for all his life Answer:  The correct answer is A. The only established possible cure for WAS is hematopoietic stem-cell transplantation (HSCT), either from bone marrow, peripheral blood or cord blood transplant (CBT) [5–7]. The four potential donor types are [7, 8]: 1. Matched sibling donor: The outcomes using an HLA-identical sibling donor bone marrow are excellent with an overall success rate approaching 90% in most centers. 2. An HLA-matched unrelated donor: Rate of favorable outcome using cells from an HLA-matched unrelated donor reaches those obtained with matched sibling donors with improvements in conditioning regimens and supportive care. 3. Haploidentical donor (half-matched, typically a parent): Transplant with cells from a haploidentical (half-matched) donor is successful in only approximately 50% of cases. 4. Fully or partially matched cord blood stem-cells: Transplants using fully or partially matched cord have also been quite successful The patients remain on immunosuppressant medications, for a period of time after transplant, in order to decrease the risk of GVHD. The more closely HLA-­ types matching exists between the donor and recipient, the less are the risks of transplant rejection and GVHD. Gene therapy is an approach whereby a normal copy of the WAS gene is delivered into the patient’s own bone marrow cells using a virus. The blood cells coming from the bone marrow are then able to make normal WASp protein. There is no risk for GVHD, since the patient’s own cells are being modified [9, 10]. One major risk of gene therapy is the oncogenic potential of the viral DNA inserted into the patient’s chromosomes. Recently, a small number of patients with WAS were successfully treated with gene therapy, correcting their bleeding problems and immune deficiency. Unfortunately, three patients developed T cell leukemia and one developed myelodysplasia followed by acute myeloid leukemia as a result of the gene therapy [8]. Studies are underway to test new gene therapy viruses that are potentially safer and to develop alternative non-viral gene therapy methods. The above problems remain to be solved before gene therapy becomes more broadly applicable [10].

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Practical Points • Atopic symptoms and early-onset eczema are frequent findings in patients with Wiskott-Aldrich syndrome • Milk allergy and other food allergies are also associated with eczema in Wiskott-Aldrich syndrome • Eczema may worsen in the presence of infections and during the winter

References 1. Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2011;18(1):42–8. 2. Thrasher AJ. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program. 2009;2009:132–8. 3. Blundell MP, Worth A, Bouma G, Thrasher AJ. The Wiskott-Aldrich syndrome: the actin cytoskeleton and immune cell function. Dis Markers. 2010;29(3–4):157–75. 4. Notarangelo LD, Ochs HD. Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation. Curr Opin Immunol. 2003;15(5):585–91. 5. Loyola Presa JG, de Carvalho VO, Morrisey LR, Bonfim CM, Abagge KT, Vasselai A, Marinoni LP. Cutaneous manifestations in patients with Wiskott-Aldrich syndrome submitted to haematopoietic stem cell transplantation. Arch Dis Child. 2013;98(4):304–7. 6. Filipovich AH, Stone JV, Tomany SC, Ireland M, Kollman C, Pelz CJ, Casper JT, Cowan MJ, Edwards JR, Fasth A, Gale RP, Junker A, Kamani NR, Loechelt BJ, Pietryga DW, Ringden O, Vowels M, Hegland J, Williams AV, Klein JP, Sobocinski KA, Rowlings PA, Horowitz MM. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97(6):1598–603. 7. Knutsen AP, Steffen M, Wassmer K, Wall DA. Umbilical cord blood transplantation in Wiskott Aldrich syndrome. J Pediatr. 2003;142(5):519–23. 8. Buchbinder D, Nugent DJ, Fillipovich AH.  Wiskott–Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55–66. 9. Passerini L.  Gene/cell therapy approaches for immune dysregulation polyendocrinopathy enteropathy X-linked syndrome. Curr Gene Ther. 2014;14(6):422–8. 10. Frecha C, Toscano MG, Costa C, Saez-Lara MJ, Cosset FL, Verhoeyen E, Martin F. Improved lentiviral vectors for Wiskott-Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis. Gene Ther. 2008;15(12):930–41.

Chapter 134

Allergy and Recalcitrant Wart Marzieh Tavakol

A 7-year-old girl was referred to the hospital with dyspnea and cough. She had experienced chronic recurring events of cough and dyspnea since 18-month-­old. Although she had been treated with inhaled corticosteroid and as-needed short-­ acting beta agonist, she had been suffering from several attacks of asthma that caused emergency department visits and recurrent admission to the hospital. She was born from consanguineous parents and did not have other siblings. There was a positive familial history of allergic disorders. She had experienced atopic eczema which was intractable and refractory to treatment starting from early weeks of her life. She was discovered to be allergic to cow’s milk protein on the basis of a positive skin prick test. However, her atopic dermatitis was not under control even with strict avoidance from dairies. Skin lesions were extensively superinfected with herpes accompanied by eye involvement, and she was admitted to the hospital with the impression of eczema herpeticum when she was 4-year-old. Her history was also positive for recurring pneumonias and disseminated troublesome warts which were intractable and unresponsive to standard treatment (Fig. 134.1). Q1. Which statement is correct? A. All of the clinical manifestations can be explained by milk protein allergy B. Although she is allergic to food protein it can not explain the clinical picture

M. Tavakol (*) Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran Department of Allergy and Clinical Immunology, Shahid Bahonar Hospital, Alborz University of Medical Sciences, Karaj, Iran Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_134

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Fig. 134.1  Skin xerosis and warts in a 7-year-old girl

C. Finding the specific IgE on radioallergosorbent test is essential to make the final diagnosis D. Non-adherence to treatment completely explains the clinical history Answer:  The correct answer is B. Atopic patients are susceptible to bacterial and viral infections which can be attributed to high expression T helper 2 -derived cytokines, elevated total and specific IgE and suboptimal function of their innate immunity. Eczema herpeticum is the most frequent and eczema vaccinatum is the most ominous cutaneous superinfection in these patients. Lesions are often heavily colonized with Staphylococcus aureus [1]. Atopic patients presenting with recurrent and intractable or unusual infections, should prompt evaluation for possible primary immunodeficiency diseases [2]. Extensive herpes, widespread wart lesions, and recurrent hospitalization due to pneumonia could not be explained by mere atopy in our patient. In her laboratory examinations, she had elevated eosinophil percentage in peripheral blood (26.3%), IgG: 1289 mg/dL (reference range 500–1300), IgA: 231 mg/dL (reference range 41–297), IgM 90% of patients with AD-HIES [3]. Our patient’s absolute blood eosinophil count was 1131/μL that is compatible with moderate eosinophilia. Considering the fact that many other allergic and non-allergic conditions are associated with high peripheral blood eosinophil count, eosinophilia does not count as a reliable finding for the diagnosis of AD-HIES. There are two other forms of HIES caused by mutations in dedicator of cytokinesis 8 (DOCK8) and Tyrosine kinase 2 (TYK2) genes, which are classified as autosomal recessive hyper-IgE syndrome (AR-HIES) [6]. Dock8 protein has a distinct role in maintenance of the immune cells cytoskeleton. DOCK8 deficiency impairs immigration of dendritic cells to the regional lymph nodes, interferes with T, B, and NK cells activity and reduces their life span [7]. DOCK8 is also expressed in several organs including pulmonary, renal, pancreatic, and cardiac cells as well as skeletal muscles, explainning the multisystem manifestations of the AR-HIES as a primary immunodeficiency syndrome [8]. Allergic manifestations are more common in DOCK8 deficient patients compared to AD-HIES. In other words, patients with DOCK8 deficiency express a wider spectrum of allergic features including food allergy, anaphylaxis and asthma with a substantially higher prevalence [9, 10]. A distinctive feature of patients with DOCK8 deficiency is unique susceptibility to viral infections including herpes simplex and varicella zoster virus, human papillomavirus, cytomegalovirus and molluscum contagiosum [7, 8, 10]. The history of eczema herpeticum with eye involvement in our patient that led to the hospital admission, along with extensive recalcitrant warts were valuable clues in agreement with the diagnosis of DOCK8 deficiency.

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Q3. Which statement is correct regarding DOCK8 deficiency? A. This syndrome is mainly diagnosed by clinical criteria B. Genetic analysis is necessary to confirm the diagnosis C. Malignancy is not a characteristic feature is these patients D. Food avoidance does not have any role in management of these patients Answer:  The correct answer is B. Although the clinical presentation is usually enough to establish the diagnosis [7], we ordered genetic testing proved the diagnosis of DOCK8 deficiency type of AR-HIES in this patient. Q4. All of the following treatment strategies are indicated in this patient, except: A. Monthly infusion of intravenous immunoglobulin B. Strict food avoidance and standard treatment of asthma C. Hematopoietic stem cell transplantation D. Prophylaxis against bacterial, viral and fungal infections Answer:  The correct answer is A. Optimal treatment of allergic manifestations, preventive measures to decrease the infections and prompt treatment are crucial in management of patients with HIES. Early hematopoietic stem cell transplantation (HSCT) can reduce the risk of malignancy and is therefore of fundamental importance [4, 7]. The patient was referred for bone marrow transplantation. Practical Points • Severe atopic dermatitis, recurrent skin and pulmonary infections that lead to abscess formation and elevated IgE serum level are main manifestations of hyper-IgE syndrome • Mutations in DOCK8 and TYK2 genes lead to autosomal recessive hyperIgE syndrome • Dock8 deficiency impairs immigration of dendritic cells to regional lymph nodes, interferes with T, B, and NK cells activity and reduces their life span

References 1. Ong PY, Leung DY. Bacterial and viral infections in atopic dermatitis: a comprehensive review. Clin Rev Allergy Immunol. 2016;51(3):329–37. 2. Pichard DC, Freeman AF, Cowen EW. Primary immunodeficiency update: part I. Syndromes associated with eczematous dermatitis. J Am Acad Dermatol. 2015;73(3):355–64. 3. Yong PF, Freeman AF, Engelhardt KR, Holland S, Puck JM, Grimbacher B. An update on the hyper-IgE syndromes. Arthritis Res Ther. 2012;14(6):228. 4. Mogensen TH.  Primary immunodeficiencies with elevated IgE.  Int Rev Immunol. 2016;35(1):39–56.

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5. Freeman AF, Olivier KN.  Hyper-IgE syndromes and the lung. Clin Chest Med. 2016;37(3):557–67. 6. Zhang Q, Su HC.  Hyperimmunoglobulin E syndromes in pediatrics. Curr Opin Pediatr. 2011;23(6):653–8. 7. Biggs CM, Keles S, Chatila TA. DOCK8 deficiency: insights into pathophysiology, clinical features and management. Clin Immunol. 2017;181:75–82. 8. Rezaei N, Hedayat M, Aghamohammadi A, Nichols KE. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. J Allergy Clin Immunol. 2011;127(6):1329–41. e2 9. Freeman AF, Holland SM.  Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29(3–4):123–30. 10. Su HC.  DOCK8 (Dedicator of cytokinesis 8) deficiency. Curr Opin Allergy Clin Immunol. 2010;10(6):515–20.

Chapter 135

Recurrent Cutaneous and Sinopulmonary Infections Angela Chang and Aisha Ahmed

A 16-year-old girl is hospitalized for pneumonia and the immunology team is consulted due to her history of recurrent skin and sinopulmonary infections. Yesterday, she developed fever to 39.4 °C, coughing, and tachypnea. She presented to the emergency room where initial laboratory investigation revealed a CBC remarkable for elevated WBC 16,000 cells/μL, absolute neutrophil count of 9000/ μL and absolute eosinophil count of 1150/μL. Blood culture is pending. Computed tomography (CT) scan of the chest shows a consolidation in the left lower lobe as well as pneumatoceles and bronchiectasis (Fig. 135.1). Q1. Pneumatoceles can occur as a result of a varying etiologies. Which differential diagnosis is least likely in this patient? A. Mechanical trauma B. Hyper IgE syndrome C. Cystic fibrosis D. Pulmonary aspergillosis Answer:  The correct answer is A. Pulmonary pneumatoceles are thin-walled, air-filled cysts that develop within the lung as a sequela to acute pneumonia. Staphylococcus aureus is a common culprit. Noninfectious etiologies include hydrocarbon ingestion, trauma, and positive pressure ventilation [1]. However, given the presence of bronchiectasis, an infectious etiology is more likely.

A. Chang Division of Pediatric Allergy, Immunology and Bone Marrow Transplant, UCSF, San Francisco, CA, USA A. Ahmed (*) University of California, San Francisco, San Francisco, CA, USA © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_135

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Fig. 135.1  Chest CT scan showing bilateral pneumatoceles and bronchiectasis in the lingula and left lower lobe in a 16-year-old girl

She is hospitalized to receive parenteral antibiotics and supplemental oxygen. Parents provide her past medical history and report that she has had frequent infections her entire life. Starting at 1 month of life, she had “baby acne” characterized by pustules with yellow crusting. She was treated with a course of cephalexin. Soon after, she was diagnosed with eczema at 3 months and was started on topical hydrocortisone 1%. Her eczema has persisted since then and now requires triamcinolone 0.1% ointment. At 12  months, she developed a 3  cm × 3  cm cervical abscess which grew Staphylococcus aureus in culture. She has continued to get 1–2 skin abscesses every year that have generally responded to trimethoprim-sulfamethoxazole. As an infant, she had frequent ear infections requiring tympanostomy tube placement at 18 months and again at 3 years. She gets 1–2 sinus infections a year requiring antibiotic treatment. When she was 8 years old, she developed severe pneumonia requiring a 2-week hospitalization for intravenous antibiotics and supplemental oxygen. Parents report that she is the only child and the family history is unremarkable. They state that she is a good student, but has missed a lot of school due to frequent infections. She is also an excellent gymnast due to her petite height and flexibility. However, last year she fractured her right forearm during a practice. On physical exam, vital signs are remarkable for fever to 39.2  °C, height is 147 cm ( A; p.Arg382Gln, which has been identified in the literature as a known cause of autosomal dominant hyper-IgE syndrome [4]. Q4. Which of the following conditions is not associated with STAT3 loss-of-­ function mutations? A. Chronic atopic dermatitis B. Recurrent viral skin infections C. Recurrent bacterial abscesses D. Retained primary teeth Answer:  The correct answer is B.

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Severe and recurrent cutaneous viral infections are seen in patients with DOCK8, but not seen in STAT3 mutation [3]. Atopic dermatitis, recurrent upper respiratory infections, elevated IgE and eosinophilia are common features of both DOCK8 and STAT3 deficiency. However, patients with DOCK8 mutation can be distinguished as they do not have parenchymal lung abnormalities, retained primary teeth, or pathologic fractures [5]. Furthermore, a distinguishing feature of DOCK8 deficiency is cutaneous viral infections with molluscum, herpes or varicella. The family asks about treatment options and the natural history of the disease. You state that pulmonary complications are the most common cause of death, followed by lymphoma [6]. As such, the immunology team will continue to follow her closely. Q5. What is the most appropriate chemoprophylactic agent for the patient? A. Acyclovir B. Itraconazole C. Trimethoprim-sulfamethoxazole D. Interferon gamma Answer:  The correct answer is C. In this patient, starting trimethoprim-sulfamethoxazole is sufficient at this time as she has not had any invasive fungal infections. Recombinant interferon gamma is currently being studied in some patients with STAT3 loss-of-function, but is not yet approved for this disease. These patients are not at increased risk of Herpes virus infections and do not require acyclovir prophylaxis.

Practical Points • STAT3 loss-of-function mutations results in autosomal dominant hyper IgE syndrome, autosomal dominant (AD) hyper IgE syndrome (HIES) • Main features of AD-HIES include dermatitis and recurrent skin and sinopulmonary infections • Characteristic facies as broad nose, frontal bossing, pathologic fractures, hyperextensible joints, and delayed primary tooth loss are among skeletal abnormalities seen in AD-HIES • Trimethoprim-sulfamethoxazole prophylaxis is recommended in patients with HIES

References 1. Wan-Hsiu L, Sheng-Hsiang L, Tsu-Tuan W. Pneumatocele formation in adult pulmonary tuberculosis during antituberculous chemotherapy: a case report. Cases J. 2009;2(1):8570. 2. Ma CS, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205(7):1551.

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3. Engelhardt KR, et  al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124(6):1289–302. 4. Holland SM, et  al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357(16):1608–19. 5. Woellner C, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(2):424–32. 6. Leonard G, et al. Non-Hodgkin’s lymphoma in Job’s syndrome: a case report and literature review. Leuk Lymphoma. 2004;45(12):2521–5.

Chapter 136

Cold Abscesses and Lymphadenopathy María Claudia Ortega-López

A 2-year-old girl born from non-consanguineous mulatto parents, was referred to our allergy clinic for workup of her recurrent cold abscesses and infections. From 10 months of age, she had developed cold abscesses with recurrent and persistent cervical, submaxillary, submandibular and inguinal lymphadenopathy, without any documented fever. Oral candidiasis, generalized cervical, submental and parietal adenopathies were also noted. During these years she had required surgical drainage of her abscess for about 17 times. She had no dental or bone abnormalities to date. In her past medical history she had asthma and allergy to cow’s milk protein. She also had moderate pulmonary hypertension, which was under control with medications and also had pneumonia at 2, 3 and 12 months. Vaccinations were up to date without any complication. Importantly, her father presented generalized abscesses and recurrent pneumonia until the school age, yet had improved since 9  years old. Her mother, uncle and grandmother had asthma and her elder brother was healthy at 11  years old. The reminder of her physical examination were unremarkable. Laboratory studies at 11 months old reveled: IgE: 1502 IU/mL, IgA: 85 mg/dL, IgG: 1578  mg/dL, and IgM: 193–294  mg/dL.  Sweat chloride test was normal. Dihydrorhodamine test from mother and patient were normal. From her CBC, eosinophils were 600/μL. Staphylococcus aureus were found in cultures of abscessed lesions. Neck TAC show abscessed adenopathies. Dental panoramic radiography was normal.

M. C. Ortega-López (*) Alejandra Ortega López Foundation, University Children’s Hospital of San José Bogotá-Colombia, Bogotá, Cundinamarca, Colombia © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_136

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Q1. What is the most likely diagnosis? A. Antibody deficiency B. Chronic granulomatous disease C. Asthma with lung abscess D. Hyper IgE syndrome Answer:  The correct answer is D. Hyper IgE syndrome (HIES) commonly presents with recurrent cutaneous infections, recurrent pneumonia with formation of pneumatoceles and elevated IgE levels [1]. Q2. Mutation in which of the following genes are more likely associated with her condition? A. STAT3 and DOCK8 B. IL17R and IL22R C. ATM and WAS D. NBS and TYK2 Answer:  The correct answer is A. Hypomorphic mutations occur in the STAT3 gene located on chromosome 17q21, are responsible for AD-HIES syndrome (OMIM147060). In patients with AR-HIES, there is a null mutation TYK2 (OMIM 611521) or a mutation homozygous in the DOCK8 gene (OMIM 611432) [2, 3]. Q3. What is the best treatment option in this patient? A. Antibiotics including antifungals B. Surgical drainage C. Intravenous immunoglobulins D. Hematopoietic stem-cell transplantation E. Answers A and B are correct Answer:  The correct answer is E. Treatment is directed towards prevention and management of infections by using sustained systemic antibiotics and antifungals along with topical therapy for eczema and drainage of abscesses. Anti-staphylococcal antibiotic prophylaxis is useful. Interferons, immunoglobulin supplementation or low-dose cyclosporine A, have been reported to benefit selected patients, but are not generally indicated [4].

Practical Points • Treatment of hyper IgE syndrome (HIES) is directed towards prevention and management of infections by using sustained systemic antibiotics and antifungals • Anti-staphylococcal antibiotic prophylaxis is indicated in all HIES patients

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References 1. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972;49:59–70. 2. Grimbacher B, Holland S, Gallin J, Greenberg F, Hill S, Malech H, Miller J, O’Connell A, Puck J. Hyper-IgE syndrome with recurrent infections: an autosomal dominant. N Engl J Med. 1999;340(9):692–702. 3. Renner E, Puck J, Holland S, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky B, Grimbacher B. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144(1):93–9. 4. Grimbacher B, Holland S, Puck J. Hyper IgE syndromes. Immunol Rev. 2005;230:244–50.

Chapter 137

Recurrent Pneumonia and Fracture in the Femur Selma Scheffler-Mendoza, Juan Carlos Bustamante-Ogando, and Marco Yamazaki-Nakashimada

A 3-year-old boy was admitted to traumatology department because of left femur multi-fragmentary fracture (Fig.  137.1) without a trauma history. On physical examination, he also had poor growth, a prominent forehead, joints hyperextensibility, neurological delay, anhidrosis and pain insensitivity. Skin lesions were present as erythematous-squamous plaques over face and neck and pruritic papular erythema at limbs, trunk, and hands (Fig.  137.2a, b) and on head and scalp with Fig. 137.1  Left femur multi-fragmentary fracture in a 3-year-old boy

S. Scheffler-Mendoza · M. Yamazaki-Nakashimada (*) Immunology Department, National Institute of Pediatrics, Mexico City, Mexico J. C. Bustamante-Ogando Primary Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_137

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Fig. 137.2 (a, b) Papular erythema with scaling at arm and limbs (c) Neck and face with erythematous squamous plaques in a 3-year-old boy with multiple fractures

erythema and crust (Fig. 137.2c), all consistent with atopic dermatitis. Relevant past medical history included neonatal sepsis at birth, severe atopic dermatitis and cow’s milk protein allergy diagnosed from 3-months old, three previous episodes of severe pneumonia requiring IV antibiotics and mechanical ventilation, once. He had received immunizations during the first year of life without adverse events and his parents reported of an uneventful pregnancy and no relevant family history. Initial immunologic workup revealed lymphopenia, eosinophilia, elevated serum IgE (>2000 UI/mL) with normal IgG, IgM, and IgA. Patient had a Grimbacher score [1] of 51 points based on: (a) serum-IgE level >2000 UI/mL (10 points), (b) >3 pneumonia episodes (8 points), (c) Fractures with minor trauma (8 points), (d) eosinophil count >800/μL (6 points), (e) severe eczema (4 points), (f) >6 respiratory infections per year (4 points), (g) hyperextensibility (4 points) and (h) appearance of symptoms below 1 year-old with young-age correction (7 points). Q1. What is the most likely diagnosis? A. Severe atopic dermatitis and vitamin D deficiency B. Autosomal dominant hyper-IgE syndrome C. Autosomal recessive hyper-IgE syndrome D. Wiskott-Aldrich syndrome E. Inborn error of metabolism Answer:  The correct answer is B. Hyper IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by elevated IgE, eczema and recurrent infections [2]. Both autosomal dominant and autosomal recessive forms have been described. Patients with autosomal dominant (AD)-HIES usually present recurrent skin boils, cyst-forming pneumonias, and marked serum IgE elevations. Other common manifestations include eczema, mucocutaneous candidiasis, eosinophilia, and non-immunologic manifestations including connective tissue, vascular and skeletal abnormalities [1, 3, 4]. Although rare, HIES should be considered as a differential diagnosis in infants with severe eczema and marked elevations in serum IgE, given that an early diagnosis could

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prevent complications and improve patient’s quality of life. Family history, associated infections and non-immunological manifestations may be important diagnostic clinical clues. Q2. Which of the following tests would help confirm this diagnosis? A. STAT3 gene sequencing B. Skin prick tests and serum vitamin D levels C. DOCK8 gene sequencing D. Metabolic panel E. WASp expression by flow cytometry analysis Answer:  The correct answer is A. AD-HIES is caused by loss-of-function mutations in Stat3 STAT3 molecule, which is a major signal transduction protein involved in diverse pathways such as wound healing, immunity, cancer, and vascular remodeling, which explains the clinical spectrum of this syndrome [4, 5]. Sequencing of the STAT3 gene is the confirmatory test for AD-HIES [6]. Around 95% of patients with clinical AD-HIES do have an identifiable STAT3 pathogenic variant. STAT3 protein expression analysis has limited value for diagnosis, as the majority of mutations lead to expression of variable amounts of non-functional protein [4, 7]. A mutation change mutation for pathogenic variant in exon 13 of STAT3 gene was confirmed in this patient. Q3. What is classic triad of STAT3 deficiency? A. Eczema, recurrent skin and lung infections, and elevated serum IgE B. Eczema, recurrent infections, and bleeding C. Eczema, food allergy, and high serum IgE D. Recurrent skin and lung infections, fractures, and elevated serum IgE E. Eczema, mental retardation, and elevated serum IgE Answer:  The correct answer is A. Diagnosis of AD-HIES requires high index of clinical suspicion. There has been described a vast spectrum of manifestations in this primary immunodeficiency. The classic triad is recurrent skin and lung infections, eczema and high serum IgE, are usually the main causes for initial consultation in these patients [4]. Other manifestations include skeletal, connective tissue, vascular system, heart, lung, and brain complications [2, 8]. A characteristic facial appearance typically emerges in adolescence. There is a clinical scoring system including both immunologic and non-­ immunologic features of AD-HIES, developed to facilitate diagnosis [4, 9]. A HIES score >40 points is highly suggestive for AD-HIES, 20–40 points is considered indeterminate, and A, V637M) in the SH2 domain was found in STAT3 gene corroborating autosomal dominant hyper IgE syndrome (AD-HIES). As is usual in the natural history of Job’s syndrome, our patient continued to experience eczema, high levels of IgE, cold skin abscesses and pneumatocele as consequences of recurrent pneumonia. So far, the patient has good control of immunological features with the use of antibiotics and monthly immunoglobulin. Our patient experienced a fracture upon minimal trauma at 12-months-old and by 6 years of age he suffered a total of five fractures. Following a left femoral fracture that caused significant restriction in range of motion, a magnetic resonance imaging was performed showing osteopenia and osteonecrosis of the left femoral head. He was treated with bisphosphonate in three doses every 6 months. A year and a half later, the orthopedic service performed an arthroplasty. By 10 years of age, the patient had restored bone density and pain had resolved. He stands and walks independently without suffering other fractures.

J. C. Alcántara-Montiel · L. Santos-Argumedo (*) Department of Molecular Biomedicine, Center for Research and Advanced Studies (CINVESTAV), National Polytechnic Institute (IPN), Mexico City, Mexico e-mail: [email protected] A. T. Staines-Boone Clinical Immunology Department, Hospital de Especialidades, Mexican Social Security Institute (IMSS), Monterrey, Nuevo Leon, Mexico © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_138

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Q1. Which of the following clinical features can be useful to distinguish the autosomal dominant form from autosomal recessive hyper-IgE syndrome? A. Eczema B. Pneumonia C. Fractures with minimal trauma D. High IgE levels E. Skin abscesses Answer:  The correct answer is C. The most significant features in this patient are fractures with minimal trauma and presence of scoliosis and pneumatoceles, which are all compatible with the autosomal dominant form of HIES. In contrast, in autosomal recessive form of hyper IgE caused by DOCK8 deficiency, severe viral infections and allergies are common [1]. Shared features include eczema, skin abscesses, upper and lower respiratory tract infections, mucocutaneous candidiasis and high serum IgE levels [2]. Q2. All of the following statements are true regarding the pathology of pneumatoceles in patients with hyper IgE syndrome, except? A. Pneumatocele is a key feature of DOCK8 deficiency B. Pneumatoceles form as a result of increased expression of MMP-8 and MMP-9 C. STAT3 deficiency is associated with an altered pattern of tissue remodeling D. Recurrent pneumonia episodes are the underlying pathology of pneumatoceles E. Usually more than one pneumatocele is present in patients Answer:  The correct answer is A. The presence of pneumatoceles after recurrent cases of pneumonia is a frequent complication in STAT3 deficiency and is rarely seen in DOCK8 deficiency. STAT3 deficiency confers altered tissue remodeling in terms of upregulated matrix metalloproteinase 8 and 9 (MMP-8 and MMP-9). These metalloproteinases are also important in lung tissues remodeling by degradation of collagen and extracellular matrix [3]. Q3. True or False: Antimicrobial prophylaxis is recommended in hyper IgE syndrome? A. True B. False Answer:  The correct answer is A. Patients with HIES are at increased susceptibility to S. aureus, P. aeruginosa, Aspergillus spp. and Candida spp. These pathogens represent a major source of morbidity in these patients. Although the regimens vary significantly between physicians, antibiotics prophylaxis is one of the pillars of therapy not only in Job’s syndrome but also in other primary immunodeficiencies [4, 5]. Q4. What is the underlying pathophysiology of fractures with the minimal trauma in AD-HIES? A. Increase local production of prostaglandin E B. Normal bone metabolism

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C. Increase in osteoblast activity D. Loss of vitamin D function on osteoclast E. Increase in osteoclast activity Answer:  The correct answer is E. It is suggested that the osteopenia in patients with STAT3 deficiency result from increased osteoclast activity. Frequent fractures and osteopenia seen in these patients is likely multifactorial and due to the effect of increased osteoclast activity, bone metabolism, and nutritional deficiencies [6, 7]. Q5. True or False: Bone densitometry is a useful tool in follow-up of patients with AD-HIES. A. True B. False Answer:  The correct answer is A. Bone densitometry is an important tool in follow-up in patients with STAT3 deficiency, however, there is a lack of correlation between fractures and normal bone mineral density. To our knowledge, there is only one study in STAT3 deficiency that associates fractures and radial bone mineral density in cortical bone of the radius, but not in hip or spine [8]. Practical Points • The autosomal dominant form of hyper IgE syndrome (HIES) has both immunologic and non-immunologic features • Osteopenia, fractures with minimal trauma and scoliosis are the most frequent non-immunological features of HIES • Treatment with bisphosphonates increases bone mineral density, at least in short-­term follow up in patients with autosomal dominant HIES

References 1. Engelhardt KR, Gertz ME, Keles S, Schaffer AA, Sigmund EC, Glocker C, Saghafi S, Pourpak Z, Ceja R, Sassi A, Graham LE, Massaad MJ, Mellouli F, Ben-Mustapha I, Khemiri M, Kilic SS, Etzioni A, Freeman AF, Thiel J, Schulze I, Al-Herz W, Metin A, Sanal O, Tezcan I, Yeganeh M, Niehues T, Dueckers G, Weinspach S, Patiroglu T, Unal E, Dasouki M, Yilmaz M, Genel F, Aytekin C, Kutukculer N, Somer A, Kilic M, Reisli I, Camcioglu Y, Gennery AR, Cant AJ, Jones A, Gaspar BH, Arkwright PD, Pietrogrande MC, Baz Z, Al-Tamemi S, Lougaris V, Lefranc G, Megarbane A, Boutros J, Galal N, Bejaoui M, Barbouche MR, Geha RS, Chatila TA, Grimbacher B. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2015;136(2):402–12. 2. Alcantara-Montiel JC, Staines-Boone T, Lopez-Herrera G, Espinosa-Rosales F, Espinosa-­ Padilla SE, Hernandez-Rivas R, Santos-Argumedo L.  Functional characterization of two new STAT3 mutations associated with hyper-IgE syndrome in a Mexican cohort. Clin Genet. 2016;89:217–21.

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3. Sekhsaria V, Dodd LE, Hsu AP, Heimall JR, Freeman AF, Ding L, Holland SM, Uzel G. Plasma metalloproteinase levels are dysregulated in signal transducer and activator of transcription 3 mutated hyper-IgE syndrome. J Allergy Clin Immunol. 2011;128(5):1124–7. 4. Freeman AF, Holland SM. Antimicrobial prophylaxis for primary immunodeficiencies. Curr Opin Allergy Clin Immunol. 2009;9(6):525–30. 5. Aguilar C, Malphettes M, Donadieu J, Chandesris O, Coignard-Biehler H, Catherinot E, Pellier I, Stephan JL, Le Moing V, Barlogis V, Suarez F, Gerart S, Lanternier F, Jaccard A, Consigny PH, Moulin F, Launay O, Lecuit M, Hermine O, Oksenhendler E, Picard C, Blanche S, Fischer A, Mahlaoui N, Lortholary O. Prevention of infections during primary immunodeficiency. Clin Infect Dis. 2014;59(10):1462–70. 6. Freeman AF, Holland SM. Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. Pediatr Res. 2009;65(5 Pt 2):32R–7R. 7. Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006;12(1):17–25. 8. Sowerwine KJ, Shaw PA, Gu W, Ling JC, Collins MT, Darnell DN, Anderson VL, Davis J, Hsu A, Welch P, Puck JM, Holland SM, Freeman AF. Bone density and fractures in autosomal dominant hyper IgE syndrome. J Clin Immunol. 2014;34(2):260–4.

Chapter 139

Cough and Dyspnea Javad Ghaffari

A 16-year-old Iranian boy presented with cough and dyspnea since several years ago (Fig. 139.1). His symptoms began during the second of year life, often accompanied by wheezing, back pain and nasal congestion. He also experienced several episodes of severe skin infections such as folliculitis and fronculitis, with positive culture for Staphylococcus aureus. His past medical history also revealed several hospital admissions due to pneumonia and recurrent otitis media, treated with intravenous antibiotics. He was born as the fifth child of healthy distantly related parents via normal vaginal delivery weighing 3 kg at birth. Shedding of primary teeth after 12 years old

Fig. 139.1  Coarse facial with clubbing in a boy with cough and dyspnea

J. Ghaffari (*) Mazandaran University of Medical Sciences, Sari, Iran © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_139

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Fig. 139.2  Bronchiectasis and multiple pneumatoceles (arrows) (a), and axial CT scan of the chest, pulmonary window showing an inflammatory cyst in the upper lobe of the left lung complicated by fungal infection (b), in a boy with cough and dyspnea

and generalized pruritic skin lesions was also reported by parents. There was no family history of similar conditions. On examination, he had apparent delayed puberty (tanner stage 3) and scoliosis that was confirmed by X-ray of spinal column. His height and weight were both under fifth percentile. Lung high resolution CT scan showed diffuse bilateral reticular injection often in middle and upper lobes associated with multiple pneumatoceles (Fig.  139.2). Pansinusitis was observed in nasal X-ray. Finally, spirometry showed mixed restrictive and obstructive patterns. Leukocyte chemotaxis assay was normal. Immunologic laboratory test results showed in Table 139.1. Q1. What is the most likely diagnosis? A. X-linked lymphoproliferative disease B. Hyper-IgE syndrome C. Common variable immunodeficiency disease D. Chronic granulomatous disease Answer:  The correct answer is B. Hyper IgE syndrome (HIES) is a rare primary immune deficiency (incidence 1/100000–1/200000), characterized by increased serum levels of IgE, eczema, recurrent cutaneous and pulmonary infections [1]. Most cases of HIES are sporadic. Usual manifestations of autosomal dominant type of HIES, caused by STAT3 mutations include, newborn rash, coarse facial features, short stature, early osteoporosis, frequent fractures, scoliosis, mucocutaneous candidiasis in form of thrush, vaginal candidiasis or candida nail infection, craniosynostosis, hyper flexible joints, eczema, delay shedding of primary teeth, and recurrent bacterial infections as skin abscesses and pneumonia associated with pneumatoceles [2]. Other poorly described features are susceptibility to malignancies, arterial malformation, central nervous system haemorrhage, and Arnold-Chiari malformation [1, 3–6].

139  Cough and Dyspnea Table 139.1  Laboratory tests results of a 3-year-old boy with multiple fractures

749 Total IgG: 2500 mg/dL IgG1: 1650 mg/dL IgG2: 600 mg/dL IgG3: 150 mg/dL IgG4: 100 mg/dL IgA: 148 mg/dL IgM: 160 mg/dL CH50(c3b): 135 mg/dL IgE: 5000 IU/mL

WBC: 12000/μL EOS: 600/μL NBT: 96% CD3: 59% CD4: 32% CD8: 27% CD19: 10% Anti-A: 1/64 Anti-B: negative

Laboratory abnormalities in HIES are eosinophilia and elevated serum IgE level. IgE level may differ from patient to patient, but is typically over 2000 IU/mL during childhood and might regress to normal levels during adulthood. IgE level below 2000 IU/mL in our case was compatible with regression toward normal values in early adolescent. Facial features include frontal bossing, broad nose and prominent lower lip that were observed in our case. In addition, he had delayed shedding of primary teeth, kyphosis and two incidents of extremity fractures, all explicable under autosomal dominant (AD)-HIES criteria. Chronic granulomatous disease (CGD) does not cause dermatitis as severe as seen in HIES and lacks the facial and skeletal abnormalities associated with AD-HIES. Patients with CGD do not develop pneumatoceles, although staphylococcal pneumonias are common, and their hallmark clinical features are granulomatous lesions involving multiple organs [1, 7]. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) can be distinguished from HIES by early-onset, insulin-dependent diabetes mellitus, severe enteropathy with watery or bloody diarrhea, failure to thrive, extensive food allergy, and erythroderma/alopecia. Nonetheless both disorders (HIES and IPEX) are associated with eczema and increased serum IgE level. IPEX is an X-linked recessive disorder associated with mutation of FOXP3, resulting in impaired development of CD4+CD25+ regulatory T cells in the thymus and impaired peripheral tolerance. These patients are typically ill since early infancy [8]. The diagnosis of standard HIES is based on clinical suspicion. Diagnosis is easier using NIH scale that is composed of 21 signs [1]. Positive family history of HIES and scoring equal or above 40 suggests diagnosis of HIES. Scores from 20 to 40 are considered as intermediate scores and score less than 20 are suggested unlikely of HIES diagnosis. Determining mutations in either of the three genes, STAT3, DOCK8 and TYK2 that are responsible for HIES can confirm the diagnosis. Q2. What is the most common pulmonary complication in this disorder? A. Asthma B. Bacterial infection C. Viral infection D. Malignancy Answer:  The correct answer is B.

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Recurrent bacterial pneumonia are often encountered in AD-HIES patients, associated with Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenza [9]. Fungal lung infections, especially with Aspergillus fumigatus, are also common. Tissue-destructing infections in AD-HIES may give rise to pneumatocele formation which is a distinguishing feature of AD-HIES with STAT3 mutation. Recurrent lung infections with both gram-positive and gram-negative bacteria are common in autosomal recessive (AR)-HIES patients with DOCK8 deficiency, and might lead to chronic lung disease with bronchiectasis. Q3. What is the major underlying pathology in this disorder? A. STAT3 gene with increased IgE and eosinophilia B. B cell-linker protein (BLNK) gene with neutrophilia and leukocytosis C. Autoimmune regulator (AIRE) gene with increased IgG, IgA and IgM D. Cytochrome b558 α chain (gp91phox) gene with abnormal nitroblue tetrazolium test Answer:  The correct answer is A. Dominant negative mutations in STAT3 (mostly in the SH2 and DNA binding domains) are identified as causes of AD-HIES [10]. Increased serum IgE concentrations, usually above 2000 IU/mL, and eosinophil levels above 90%, are present in both forms of the HIES. IgE levels may normalize or decrease in adulthood. Total WBC counts are typically normal in patients with STAT3 mutations but do not show appropriate increase during acute infection. Neutropenia is uncommon. Decrease levels of CD45RO+ central memory T cells and CD27+ memory B cells have also been noted. Serum IgG, IgA, and IgM levels are typically normal, although some individuals with AD-HIES have deficiencies in one or more of these immunoglobulin subtypes, especially IgA. AR-HIES patients with DOCK8 deficiency typically exhibit very high eosinophil numbers in the peripheral blood in the face of severely low number of T cells. They manifest low serum IgM levels and fail to sustain specific antibody responses upon vaccination [1, 11]. Q4. What option best describes non-immunological abnormalities in AD-HIES? A. Delayed exfoliation of primary teeth and scoliosis B. Microcephaly, hearing impairment and Ataxia C. Pyoderma gangrenosum and molluscum contagiosum D. Aplastic anaemia and telangiectasia Answer:  The correct answer is A. AD-HIES has some non-immunologic features including craniofacial, musculoskeletal, dental, and vascular abnormalities [10–12]: 1 . Increased inter alar distance, 2. Prominent forehead and chin 3. Coarse skin and facial asymmetry 4. Hyperextensibility and scoliosis 5. Minor trauma fractures and osteopenia 6. Failure to exfoliate primary teeth

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7. High arched palate, hard palate midline sagittal fibrotic thickening and deep groves 8. Vascular abnormalities including aneurysms, dilation, and tortuosity of middle-­ sized arteries, lacunar infarctions, hypertension and myocardial infarction

Practical Points • Increased serum IgE concentrations, usually above 2000  IU/mL, and eosinophil levels above 90%, are present in both forms of the hyper IgE syndrome (HIES) • Coarse facial features, short stature, early osteoporosis, frequent fractures, scoliosis, mucocutaneous candidiasis in form of thrush, vaginal candidiasis or candida nail infection, craniosynostosis, hyper flexible joints, delay shedding of primary teeth are in favour of autosomal dominant form of HIES

References 1. Ghaffari J, Ahanchian H, Zandieh F. Update on hyper IgE syndrome (HIES). J Pediatrics Rev. 2014;2(1):39–46. 2. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–55. 3. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361(21):2046–55. 4. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder. N Engl J Med. 1999;340(9):692–702. 5. Freeman AF, Collura-Burke CJ, Patronas NJ, Ilcus LS, Darnell D, Davis J, et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics. 2007;119(5):e1121–e5. 6. Freeman AF, Holland SM. Clinical manifestations, etiology, and pathogenesis of the hyper IgE syndromes. Pediatr Res. 2009;65(5 Pt 2):32R. 7. Orhan M, Ozkan Y, Irkeç M. Eye involvement in hyperimmunoglobulinemia E (Job’s) syndrome. J Pediatr Ophthalmol Strabismus. 2001;38(5):313–4. 8. Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144(1):93–9. 9. Freeman AF, Olivier KN. Hyper IgE syndromes and the lung. Clin Chest Med. 2016;37(3):557. 10. Yong PF, Freeman AF, Engelhardt KR, Holland S, Puck JM, Grimbacher B. An update on the hyper-IgE syndromes. Arthritis Res Ther. 2012;14(6):228. 11. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease: report on a national registry of 368 patients. Medicine. 2000;79(3):155–69. 12. Kliegman R. Nelson textbook of pediatrics. Philadelphia: Elsevier/Saunders; 2011. 13. Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol. 2008;122(6):1054–62. 14. Michael Blaese R, Stiehm RE, Bonilla FA, Younger ME.  Immune Deficiency Foundation patient & family handbook for primary immunodeficency diseases. 5th ed. Maryland: Immune Deficiency Foundation; 2013.

Chapter 140

Skin Abscesses, Eczema and Lymphopenia Elif Karakoc-Aydiner and Ahmet Ozen

A 13-month-old girl presented with skin abscesses and eczema at gluteal region and scalp. Past medical history revealed chronic diarrhea, recurrent fever, weight loss and recurrent infections since 1 months of age, and abscess on upper lip at 10 months of age. Parental consanguinity was remarkable at family history. Physical examination revealed mild neurodevelopmental delay, hepatomegaly and inguinal lumps without any dysmorphic or skeletal dysplasia findings. Her initial laboratory findings are represented in Table 140.1. Lymphocyte subset analysis by flow cytometry was performed due to patients’ lymphopenia, suggesting a combined immune deficiency. Results demonstrated

Table 140.1  Initial laboratory findings of a girl with skin abscesses and eczema starting at 13-months old Leukocytes/μL Lymphocytes/μL Neutrophils/μL Eosinophils/μL Hemoglobin (g/dL) Platelets/μl IgA (mg/dL) IgM (mg/dL) IgG (mg/dL) IgE IU/ml

Result 4100/μL 1200/μL 3500/μL 200/μL 10.4 (g/dL) 424,000/μL 333 (mg/dL) 107 (mg/dL) 1430 (mg/dL) 2584 (IU/ml)

References range [1] 5468–199,984 1192–9147 2128–7820 70–1076 9–14 184,208–604,302 30–307 66–228 605–1430 0.8–15

Assessment ↓ ↓ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↑

E. Karakoc-Aydiner (*) · A. Ozen Division of Allergy and Immunology, Marmara University, Istanbul, Turkey Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_140

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decreased CD3+ T cell: 43% (reference range: 51–84.1), CD3+CD4+ T helper: 16% (reference range: 29.2–58%) and CD19+ B cell: 3.3% (reference range: 13–37.7%) percentages, whereas CD3+CD8+ T cytotoxic: 26% (reference range: 14.1–31.2), and CD16+56+ NK cells: 49% (reference range: 2–26.3%) were within age-matched reference range [2]. These findings were suggestive of TlowBlowNK+ combined immunodeficiency. Further analyses to were performed to explore naïve and memory cell percentages which was decreased for naïve and elevated for memory CD4+ cell percentages: 5% (reference range: 13.7–36.9%) and 97% (reference range: 56.1–94.7%), respectively). In addition, recent thymic emigrants (CD4+CD45RA+CD31+) were decreased to 3.2% (reference: 60–83%) which is also suggestive for remarkably decreased T cell output from thymus. Ultrasonography revealed inguinal lymphadenopathies and thorax tomography showed bilateral atelectasis at upper lobes. During follow-up, she developed neutropenia (560/μL), eosinophilia (1800/μL) and direct coombs positive hemolytic anemia (Hb: 4.1 mg/dL). Q1. What is the most likely diagnosis? A. STAT3 deficiency B. Wiskott-Aldrich syndrome C. PGM3 deficiency D. DOCK8 deficiency Answer:  The correct answer is C. Hyper IgE syndromes (HIES) are known to be caused by autosomal dominant inheritance, as in the case in STAT3 deficiency and TYK2 deficiency, whereas autosomal recessive inheritance is caused by DOCK8 and PGM3 deficiencies [3]. PGM3 deficiency typically presents with recurrent respiratory and skin infections beginning in early childhood with increased serum IgE and eosinophilia. Affected individuals may also show developmental delay or cognitive impairment of varying severity [4]. PGM3 gene encodes a protein catalyzing the reversible conversion of N-acetylglucosamine-6-phosphate (GlcNAc-6-P) to GlcNAc-1-P [4]. This enzyme is crucial to assemble glycosylated proteins in various intracellular compartments, on the cell surface, in the cytoplasm, and in the extracellular matrix. As a result, syndromic manifestations of a congenital glycosylation disorder, elevated serum IgE levels, recurrent infections, and atopic features are all exhibited in the clinical synopsis of PGM3 deficiency [3]. Moreover, Stray-Pedersen and colleagues described PGM3 mutations causing severe combined immunodeficiency (SCID) phenotype due to a congenital disorder of glycosylation with neutropenia, skeletal dysplasia, and neurologic abnormalities [5]. Our patient presented here clinically demonstrated a hyper-IgE-like phenotype whereas initial laboratory findings were suggestive for combined immunodeficiency rather than a SCID phenotype. Since she had skin abscesses, dihydrorhodamine assay for neutrophils to rule out chronic granulomatous disease was performed and resulted a stimulation index (SI) of 18 for patient which was comparable to healthy subject (SI:21). Furthermore, combined immune deficiency with eosinophilia and high IgE levels are highly suggestive of

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DOCK8 deficiency. DOCK8 protein expression by flow cytometry was found to be comparable to healthy subject and gene sequencing showed no deletions or pathogenic variations. In addition, TlowBlowNK+ combined immune deficiency phenotype directed us to sequencing of RAG1 and RAG2 genes and no pathogenic variations were shown. Finally, PGM3 deficiency was confirmed for this patient by showing the homozygous deleterious mutation by sequencing (c.713T>C = p.Val238Ala) and parents were also found to be carriers for this mutation. Q2. Which of the below findings is suggestive for PGM3 deficiency in this patient? 1. Reversed CD4+/CD8+ T cell ratio 2. Neurological developmental delay 3. Skeletal dysplasia 4. chronic diarrhea A. B. C. D.

1, 3 1, 2 3, 4 2, 4

Answer:  The correct answer is B. Laboratory findings that support the diagnosis of HIES from PGM3 mutations can be summarized as lymphopenia, neutropenia, hemolytic anemia, eosinophilia, elevated IgE levels, variable IgA, IgM and IgG levels, CD3+ T cell and CD3+CD4+ T helper lymphopenia, reversed CD4+/CD8+ ratio, decreased memory B cells, decreased UDP-GlcNAc, and decreased formation of complex N-glycans [3]. As it is demonstrated in our patient, decreased number of thymic emigrant T cells may be a feature of PGM3 deficiency and should be checked in lymphocyte subsets enumeration [6]. Q3. What is the best long-term management option in this patient? A. Hematopoietic stem cell transplantation B. Antimicrobial prophylaxis C. Immunoglobulin replacement therapy D. All of the above Answer:  The correct answer is D. Treatment with intravenous immunoglobulin may reduce the severity and frequency of infections in HIES. Prophylactic use of trimethoprim-­sulfamethoxazole, anti-viral and anti-fungal drugs may also be warranted. Hematopoietic stem cell transplantation (HSCT) should also be considered in patients with SCID-like presentation and a favorable outcome. Additionally, bilateral lung transplantation for chronic lung disease and bronchiectasis, erythrocyte transfusions for comorbid hemolytic anemia, and use of granulocyte colony stimulating factor injections for co-morbid neutropenia have been reported effective in patients with PGM3 mutations [5, 6].

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Practical Points • PGM deficiency is a rare autosomal recessive disease, characterized by recurrent infections, lymphopenia, neutropenia, elevated IgE levels, eosinophilia, skeletal or neurological involvement, and reversed CD4+/CD8+ ratio • Patients present with either of the two scenarios, first; with early in life symptoms similar to severe combined immunodeficiency (SCID) phenotype and a second, later in life with hyper IgE syndrome (HIES)-like presentation • Physicians should keep in mind PGM3 deficiency in patients with negative results for relevant SCID or HIES genes in accordance to their clinical presentation and phenotype

References 1. Aksu G, Genel F, Koturoğlu G, Kurugöl Z, Kütükçüler N. Serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: a study using nephelometric technique. Turk J Pediatr. 2006;48:19–24. 2. Besci O, Ogulur O, Cicekkoku D, Kıykım A, Nain E, Boran P, Ozen A, Baris S, Karakoc-­ Aydier E. Reference values for lymphocyte subsets in healthy children and adolescent. JMF Marmara Center. ESID 2017 Meeting 2017. 3. Yang L, Fliegauf M, Grimbacher B. Hyper-IgE syndromes: reviewing PGM3 deficiency. Curr Opin Pediatr. 2014;26:697–703. 4. Stray-Pedersen A, Backe PH, Sorte HS, Morkrid L, Chokshi NY, Erichsen HC, Gambin T, Elgstoen KB, Bjoras M, Wlodarski MW, Kruger M, Jhangiani SN, Muzny DM, Patel A, Raymond KM, Sasa GS, Krance RA, Martinez CA, Abraham SM, Speckmann C, Ehl S, Hall P, Forbes LR, Merckoll E, Westvik J, Nishimura G, Rustad CF, Abrahamsen TG, Ronnestad A, Osnes LT, Egeland T, Rodningen OK, Beck CR, Boerwinkle EA, Gibbs RA, Lupski JR, Orange JS, Lausch E, Hanson IC. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am J Hum Genet. 2014;95(1):96–107. 5. Zhang Y, Yu X, Ichikawa M, Lyons JJ, Datta S, Lamborn IT, Jing H, Kim ES, Biancalana M, Wolfe LA, DiMaggio T, Matthews HF, Kranick SM, Stone KD, Holland SM, Reich DS, Hughes JD, Mehmet H, McElwee J, Freeman AF, Freeze HH, Su HC, Milner JD. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J Allergy Clin Immunol. 2014;133(5):1400–9, 9.e1-5. 6. Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, Patiroglu T, Unal E, Ozdemir MA, Jouhadi Z, Khadir K, Ben-Khemis L, Ben-Ali M, Ben-Mustapha I, Borchani L, Pfeifer D, Jakob T, Khemiri M, Asplund AC, Gustafsson MO, Lundin KE, Falk-Sorqvist E, Moens LN, Gungor HE, Engelhardt KR, Dziadzio M, Stauss H, Fleckenstein B, Meier R, Prayitno K, Maul-Pavicic A, Schaffer S, Rakhmanov M, Henneke P, Kraus H, Eibel H, Kolsch U, Nadifi S, Nilsson M, Bejaoui M, Schaffer AA, Smith CI, Dell A, Barbouche MR, Grimbacher B. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol. 2014;133(5):1410–9, 9.e1-13.

Chapter 141

Lymphopenia and Neutropenia Alexandra Langlois and Reza Alizadehfar

A term baby boy was born to Caucasian parents after an uneventful pregnancy. A CBC was performed due to a suspicion of early-onset bacterial sepsis, and demonstrated neutropenia and lymphopenia. After appropriate septic workup, the patient was put on intravenous antibiotic therapy to cover for possible bacteremia and meningitis. The patient remained clinically well. Despite the infectious workup and cultures being negative, the lymphopenia and neutropenia persisted. The patient was transferred to a referral center on the 8th day of life for further investigation of lymphopenia and neutropenia. The baby was well and did not present any respiratory distress, diarrhea or skin rashes. On physical examination, he did not show any significant dysmorphic features, skin involvement, lymphadenopathies or organomegaly. There was no consanguinity and the mother tested negative for HIV during pregnancy. His laboratory investigations demonstrated a WBC count of 3700/μL with 760/μL absolute lymphocytes, 810/μL neutrophils and 280/μL eosinophils. Hemoglobin was 18.9 g/dL and platelets were 307,000/μL. A further look at his immune system demonstrated severe B and T lymphopenia and normal NK cells numbers (Table  141.1) [1]. Spectrophenotyping of the TCR Vb repertoire was normal. Lymphocyte proliferation assay showed a very poor responses to mitogens (Table 141.2). His IgG level was 949 mg/dL while IgA, IgM and IgE were undetectable.

A. Langlois (*) · R. Alizadehfar Division of Pediatric Allergy, Dermatology and Clinical Immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_141

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Table 141.1  Lymphocyte enumeration in an 8 day-old boy with lymphopenia and neutropenia CD3 Cells/uL (%) 228 (28%) Reference range for age 4040 Median (10th–90th) (3180–5401) Absolute Lymphocyte count 760/μL

CD4 Cells/uL (%) 154 (19%) 3079 (2330–3617)

CD8 Cells/uL (%) 68 (8%) 1048 (712–1361)

CD19 Cells/uL (%) 93 (13%) 1032 (315–1383)

CD 16/56 Cells/uL (%) 426 (59%) 408 (201–870)

Table 141.2  Results of lymphocyte stimulation in an 8  day-old boy with lymphopenia and neutropenia

Unstimulated Phytohemagglutin Concanavalin A Pokeweed

Patient Cpm (SI) 1205 35 352 (29.34) 30 333 (25.17) 35 445 (29.42)

Control Cpm (SI) 861 126 366 (146.77) 108 868 (126.44) 73 113 (84.92)

Cpm Counts per minute, SI Stimulation index

Q1. What is the most likely diagnosis? A. X-linked severe combined immunodeficiency B. Adenosine deaminase deficiency C. Artemis deficiency D. PGM3 deficiency Answer:  The correct answer is D. Severe combined immunodeficiency (SCID) can result from a wide variety of genetic mutations and usually presents in the first year of life. Some cases are identified very early as a result of neonatal screening or incidental finding. Others will present with recurrent bacterial, viral, fungal or opportunistic infections, poor weight gain or chronic diarrhea amongst other signs. Lymphocyte subset phenotype of these patients might vary according to the causative mutation and the point where it affects the process of lymphocyte maturation [2, 3]. For example, X-linked SCID classically presents with a T−B+NK− phenotype because a mutation in IL2RG leads to abnormal cytokine pathway signalling. SCID due to adenosine deaminase deficiency (ADA) results in accumulation of metabolites that are toxic for lymphoid precursor and leads to a T−B−NK− phenotype. Artemis deficiency leads to abnormal V(D)J recombination, a process mandatory for T and B cell maturation but not NK cells leading to a T−B−NK+ presentation. PGM3 SCID is a rare presentation of a congenital disorder of glycosylation that presents with T−B−NK+ lymphopenia with neutropenia [4]. The patient demonstrated compound heterozygous mutations of the PGM3 gene. Parental studies confirmed that he inherited a different mutation on each allele of the gene from each parent. Patients with reticular dysgenesis also present with a SCID phenotype with neutropenia but are T−B−NK−.

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Q2. All of the following therapeutic options are appropriate management steps in SCID, except: A. Only cytomegalovirus negative, irradiated blood products should be used when necessary B. Urgent immunization of the patient and family members should be considered C. Protective isolation measures with strict hand hygiene to prevent opportunistic infections D. Antibiotic prophylaxis and intravenous immunoglobulin (IVIG) should be started promptly Answer:  The correct answer is B. The main concern in these patients is to avoid infections and to provide them with definitive treatment of their condition. Blood products need to be cytomegalovirus (CMV) negative to prevent CMV transmission. All blood products also need to be irradiated to eliminate donor lymphocytes as these lymphocytes can lead to a graft versus host disease (GVHD)-like reaction in the absence of a functional host immune system. Antibiotic prophylaxis, often trimethoprim-sulfamethoxazole, will be initiated to prevent Pneumocystis jirovecii infection. An antifungal agent like fluconazole will be added and IVIG will be administered in order to supplement their humoral defect. Immunization with live vaccines (e.g. BCG, rotavirus, MMR, varicella, live influenza) is absolutely contraindicated for the patient and his close contacts. Definitive treatments are hematopoietic stem cell transplantation (HSCT) or gene therapy [5]. Q3. Which one of these following findings is not among clinical features of PGM3 deficiency? A. Radiosensitivity B. Skeletal dysplasia C. Food allergies D. Eczema Answer:  The correct answer is A. PGM3 deficiency is an autosomal recessive disorder of glycosylation with significant phenotypic variation amongst affected individuals. It was initially described in adolescent or adult patients presenting with hyper-IgE-like phenotype [6], atopy, immunodeficiency, neurocognitive impairment and autoimmunity [7]. Other patients with this genetic defect will present early with a severe T−B−NK+ SCID and neutropenia phenotype and would die without HSCT. Some patients have also presented with skeletal dysplasia similar to Desbuquois dysplasia [4]. PGM3 has not been described as a radiosensitive SCID. Radiosensitive SCID are attributed to mutations in genes involved in non-homologous end joining in the V(D)J recombination such as Artemis, DNA-PKcs, DNA ligase 4 and Cernunnos-XLF [8]. The patient underwent a matched unrelated hematopoietic stem cell transplant from cord blood. On day 24 post-transplant, he presented with diffuse erythematous maculopapular lesions on about 75% of the body with palmoplantar involvement.

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He had feeding difficulties with significant regurgitations without bloody stools. His platelets were low (12,000–20,000/μL) and his bilirubin increased from 4 to 20 μmol/L. Q4. What is the most likely diagnosis? A. Infection B. Secondary malignancy C. Infertility D. Graft versus host disease Answer:  The correct answer is D. One of the most dramatic side effects of HSCT is acute graft-versus-host disease (GVHD) [9]. Other complications include infections, drug toxicities such as renal or liver impairment, infertility and secondary malignancy. GVHD is seen more frequently in patients receiving stem cells from donors with HLA-disparity or with unrelated donors. The most common organ affected is skin, followed by gastrointestinal tract and liver. Clinically the symptoms can range from mild to life-threatening reactions. GVHD diagnosis often requires biopsies to rule out alternative diagnoses. Q5. What is the most appropriate first-line treatment in this condition? A. Rituximab 375 mg/m2 B. Methylprednisolone 1–2 mg/Kg C. Ganciclovir 5 mg/kg D. Piperacillin-tazobactam 100 mg/Kg Answer:  The correct answer is B. The first line treatment for moderate acute GVHD is methylprednisolone. The starting dose varies from 1 to 2 mg/kg and is usually tailored to the evolution of disease. If the patient fails to show improvement in the first 3–5 days of methylprednisolone treatment, a second-line treatment is usually added. There is no definitive guideline in management of acute GVHD and different adjunctive therapies are being used. Commonly seen therapies include mycophenolate mofetil (MMF), tacrolimus, sirolimus, anti-thymocyte globulin (ATG), anti-CD52 (alemtuzumab) and antiTNF. Studies are ongoing to identify the best regimen in various clinical scenarios [9]. Practical Points • Severe combined immunodeficiency (SCID) is a life-threatening diagnosis and children presenting with lymphopenia need to be evaluated promptly • PGM3 deficiency is a rare form of T−B−NK+ SCID presenting with neutropenia • Older children and adults with PGM3 deficiency can present with an hyper-IgE-­ like phenotype often accompanied with neurological impairment

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References 1. Tosato F, Bucciol G, Pantano G, Putti MC, Sanzari MC, Basso G, Plebani M. Lymphocytes subsets reference values in childhood. Cytometry A. 2015;87(1):81–5. 2. Tasher D, Dalal I. The genetic basis of severe combined immunodeficiency and its variants. Appl Clin Genet. 2012;5:67–80. 3. Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, Conley ME, Cunningham-­ Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM, Sullivan KE, Tang ML. The 2015 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol. 2015;35(8):727–38. 4. Zhang Y, Yu X, Ichikawa M, Lyons JJ, Datta S, Lamborn IT, Jing H, Kim ES, Biancalana M, Wolfe LA, DiMaggio T, Matthews HF, Kranick SM, Stone KD, Holland SM, Reich DS, Hughes JD, Mehmet H, McElwee J, Freeman AF, Freeze HH, Su HC, Milner JD. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J Allergy Clin Immunol. 2014;133(5):1400–9, 9 e1-5. 5. Rivers L, Gaspar HB. Severe combined immunodeficiency: recent developments and guidance on clinical management. Arch Dis Child. 2015;100(7):667–72. 6. Mogensen TH.  Primary immunodeficiencies with elevated IgE.  Int Rev Immunol. 2016;35(1):39–56. 7. Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, Patiroglu T, Unal E, Ozdemir MA, Jouhadi Z, Khadir K, Ben-Khemis L, Ben-Ali M, Ben-Mustapha I, Borchani L, Pfeifer D, Jakob T, Khemiri M, Asplund AC, Gustafsson MO, Lundin KE, Falk-Sorqvist E, Moens LN, Gungor HE, Engelhardt KR, Dziadzio M, Stauss H, Fleckenstein B, Meier R, Prayitno K, Maul-Pavicic A, Schaffer S, Rakhmanov M, Henneke P, Kraus H, Eibel H, Kolsch U, Nadifi S, Nilsson M, Bejaoui M, Schaffer AA, Smith CI, Dell A, Barbouche MR, Grimbacher B. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol. 2014;133(5):1410–9, 9.e1-13. 8. Dvorak CC, Cowan MJ. Radiosensitive severe combined immunodeficiency disease. Immunol Allergy Clin N Am. 2010;30(1):125–42. 9. Carpenter PA, Macmillan ML.  Management of acute graft-versus-host disease in children. Pediatr Clin N Am. 2010;57(1):273–95.

Chapter 142

Red Peeling Ziying V. Lim and Emily Y. Gan

At birth, a neonate presented with diffuse ichthyosiform erythroderma with peeling and exfoliation (Fig. 142.1). He spent the first 7 months of his life in the hospital as he suffered from severe failure to thrive with poor nutritional status, and required tube feeding to support his growth. Of note, there was no hemidysplasia, limb

a

b

c

Fig. 142.1 (a, b) Diffuse erythroderma affecting the face, trunk and limbs, and (c) hyperkeratotic yellowish plaques on a background of erythroderma on scalp of a baby with diffuse erythroderma at 9 months of age

Z. V. Lim National Skin Centre, Singapore, Singapore E. Y. Gan (*) National Skin Centre, Singapore, Singapore Dermatology Service, KK Women’s and Children’s Hospital, Singapore, Singapore © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_142

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defects, hearing or visual impairment. He was born of a non-consanguineous marriage and there was no family history of similar findings. Genetic testing demonstrated a homozygous nonsense mutation (R350X) in exon 12 of the serine protease inhibitor, Kazal type 5 (SPINK5), resulting in the complete absence of the lympho-­ epithelial Kazal-type related inhibitor (LEKTI) protein, confirming the diagnosis of Netherton syndrome. Both parents were carriers of the SPINK5 mutation, located in the intron upstream of exon 12. A radioallergosorbent test was performed at 3 years of age and detected high levels of specific IgE antibodies to egg white, shrimp and soyabean. A multidisciplinary team consisting of a geneticist, gastroenterologist and dermatologist closely follow him up. With dutiful skin care, regular emollients and wet wrap therapy, his skin condition has remained stable over the years. He is also of average intelligence and attends a regular elementary school. Q1. What is the classic triad of Netherton syndrome? A. Congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic manifestations B. Congenital ichthyosiform erythroderma, trichorrhexis nodosa, and mental and growth retardation C. Congenital ichthyosiform erythroderma, congenital hemidysplasia, and limb defects D. Congenital ichthyosiform erythroderma, sensorineural hearing loss, and vascularizing keratitis Answer:  The correct answer is A. Patients with Netherton syndrome present at birth with generalized ichthyosiform erythroderma and sparse and brittle hair. Apart from a generalized scaling erythroderma, other cutaneous manifestations of Netherton syndrome include; ichthyosis linearis circumflexa, described as intermittent migratory serpiginous erythematous plaques with peripheral double-edged scaling [1], a pustular eruption that may mimic infantile pustular psoriasis [2], and hypertrophic papilloma in the flexural folds, especially of the groin [3]. Hair shaft abnormalities become more apparent after infancy and include trichorrhexis invaginata, pili torti and/or trichorrhexis nodosa. Trichorrhexis invaginata, or “bamboo hair”, is the classical association with Netherton syndrome where there is invagination of the distal hair shaft onto its proximal portion. Less common associations are pili torti, where the hair shaft is flattened at irregular intervals and twisted 180° along its axis, and trichorrhexis nodosa, where hair is exceptionally brittle at multiple nodes along the hair shaft [4]. Eyebrows and eyelashes are also affected [5]. Trichothiodystrophy describes a group of disorders that can present with neonatal erythroderma, and are characterized by sulfur-deficient brittle hair, trichorrhexis nodosa, and intellectual impairment. The culprit mutations are in the ERCC2/XPD gene on chromosome 19q13.2-q13.3, encoding the basal transcription/DNA repair factor IIH [6].

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CHILD syndrome is an X-linked dominant disorder characterized by congenital ichthyosiform erythroderma, congenital hemidysplasia, and limb defects caused by reduced-function mutations in the NAD (P) dependent steroid dehydrogenase-like (NSDHL) gene [7]. Keratitis-ichthyosis-deafness (KID) syndrome is a rare autosomal dominant disorder caused by heterozygous mutations in the GJB2 gene, encoding connexin 26, a gap junction protein. It presents with congenital ichthyosiform erythroderma, profound sensorineural hearing loss, and vascularizing keratitis [8]. Patients may also have multiple hyperplastic keratotic nodules that may turn dysplastic and transform into squamous cell carcinoma later in life [9]. Q2. All of the following are among complications of neonatal erythroderma, except: A. Hypernatremic dehydration B. Septicemia C. Failure to thrive D. Immunodeficiency Answer:  The correct answer is D. Apart from Netherton syndrome, neonatal erythroderma may be caused by other complex ichthyosis syndromes, immunodeficiency syndromes such as Omenn syndrome, and eczematous or papulosquamous dermatitis. Due to the extensive loss of skin barrier and increased transepidermal water loss in erythroderma, potential complications that may arise include; hypernatremic dehydration, fluid and electrolyte imbalance, temperature dysregulation, heart failure and cutaneous infections that may lead to septicemia [10]. In addition, patients with immunodeficiency are at increased risk of opportunistic infections and deep fungal infections. Nutritional loss and chronic diarrhea resulting in failure to thrive are common longer term complications of neonatal erythroderma [11]. Management of erythroderma involves preventing and addressing these potential complications. These include; prompt correction of any fluid and electrolyte imbalances, provision of good skin care for prevention of cutaneous infections, use of appropriate antibiotics, and provision of adequate nutritional support [11]. Q3. All of the following are among extracutaneous manifestations of Netherton syndrome, except: A. Growth hormone deficiency B. Recurrent systemic infections C. Pancreatic insufficiency D. Focal cataracts Answer:  The correct answer is D. Extracutaneous manifestations seen in Netherton syndrome include growth hormone deficiency [11], failure to thrive, short stature, mild developmental delay, intellectual disability, recurrent systemic infections, and pancreatic insufficiency [12].

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LEKTI is a serine protease present in cutaneous and mucosal epithelia and various endocrine glands. Deficiency of LEKTI in the pituitary gland results in a lack of inhibition of protease activity on growth hormone. Clinically, the growth retardation as a result of growth hormone deficiency has been shown to respond well to replacement therapy [11]. The pancreatic insufficiency seen in Netherton syndrome is postulated to be due to a mutation in SPINK1, a serine protease inhibitor in the pancreas, which leads to auto-digestion and therefore chronic pancreatitis. As both SPINK1 and SPINK5 are located on the same chromosome (5q31-q32), it is believed that they have a pathophysiological connection [12]. Focal cataracts are seen in Conradi-Hunermann syndrome, which is a rare genetic disorder characterized by skeletal malformations, cutaneous abnormalities, focal cataracts and short stature [13]. Q4. Patients with Netherton syndrome often have elevated IgE levels, eosinophilia and atopy. All of the following differential diagnosis can present with all three, except: A. Atopic dermatitis B. Irritant contact dermatitis C. Food allergies D. Allergic rhinitis Answer:  The correct answer is B. Atopic manifestations may first be detected in the neonatal period and include severe atopic dermatitis, allergic rhinitis, and asthma. Patients with Netherton syndrome often have multiple food allergies, ranging from mild cutaneous reactions to severe life-threatening angioedema and anaphylaxis [14]. Reduced LEKTI expression in cutaneous and sinonasal epithelium, results in unopposed protease activity and thereafter a significant barrier defect. In addition, many allergens harbor protease activity that further disrupts the epithelial barrier, resulting in allergen penetration and thus sensitization in patients with Netherton syndrome [14]. Q5. This patient’s parents are planning for a second child. What are the chances of their second child having Netherton syndrome? A. 0% B. 25% C. 50% D. 100% Answer:  The correct answer is B. Netherton syndrome is autosomal recessive in its inheritance pattern [5]. As both parents are heterozygote carriers of the SPINK5 mutation, each sibling of a patient with Netherton syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being homozygous wild type and thus unaffected.

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Practical Points • Netherton syndrome is a rare autosomal recessive disorder presenting with a generalized ichthyosiform erythroderma, characteristic hair shaft abnormality and allergic manifestations • Netherton syndrome is caused by germline mutations in the SPINK5 gene • Management of Netherton syndrome should be multidisciplinary, involving fluid and electrolyte correction, conscientious skin care with frequent application of emollients, prompt treatment of cutaneous and systemic infective complications, and nutritional support

References 1. Guerra L, Fortugno P, Pedicelli C, Mazzanti C, Proto V, Zambruno G, Castiglia D. Ichthyosis linearis circumflexa as the only clinical manifestation of Netherton syndrome. Acta Derm Venereol. 2015;95(6):720–4. 2. Mendiratta V, Yadav P, Chander R, Aggarwal S. Recurrent pustular eruption masquerading as pustular psoriasis in Netherton syndrome. Pediatr Dermatol. 2015;32(1):147–8. 3. Hovnanian A. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 2013;351(2):289–300. 4. Srinivas SM, Hiremagalore R, Suryanarayan S, Budamakuntala L. Netherton syndrome with pili torti. Int J Trichol. 2013;5(4):225–6. 5. Bitoun E, Chavanas S, Irvine AD, Lonie L, Bodemer C, Paradisi M, Hamel-Teillac D, Ansai S, Mitsuhashi Y, Taieb A, de Prost Y, Zambruno G, Harper JI, Hovnanian A. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J Invest Dermatol. 2002;118(2):352–61. 6. Hashimoto S, Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair/ transcription factor TFIIH. Hum Mol Genet. 2009;18(R2):R224–30. 7. Lai-Cheong JE, Elias PM, Paller AS. Pathogenesis-based therapies in ichthyoses. Dermatol Ther. 2013;26(1):46–54. 8. Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L.  Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002;70(5):1341–8. 9. Natsuga K, Akiyama M, Shimizu H. Malignant skin tumours in patients with inherited ichthyosis. Br J Dermatol. 2011;165(2):263–8. 10. Pruszkowski A, Bodemer C, Fraitag S, Teillac-Hamel D, Amoric JC, de Prost Y.  Neonatal and infantile erythrodermas: a retrospective study of 51 patients. Arch Dermatol. 2000;136(7):875–80. 11. Aydin BK, Bas F, Tamay Z, Kilic G, Suleyman A, Bundak R, Saka N, Ozkaya E, Guler N, Darendeliler F.  Netherton syndrome associated with growth hormone deficiency. Pediatr Dermatol. 2014;31(1):90–4. 12. Machet P, Bodemer C, Lorette G, Fraitag S, Raynaud M, Willot S, Maruani A. Exocrine pancreatic insufficiency in a child with Netherton syndrome. Eur J Dermatol. 2016;26(3):311–2. 13. Yoneda K. Inherited ichthyosis: syndromic forms. J Dermatol. 2016;43(3):252–63. 14. Hannula-Jouppi K, Laasanen SL, Heikkila H, Tuomiranta M, Tuomi ML, Hilvo S, Kluger N, Kivirikko S, Hovnanian A, Makinen-Kiljunen S, Ranki A. IgE allergen component-based profiling and atopic manifestations in patients with Netherton syndrome. J Allergy Clin Immunol. 2014;134(4):985–8.

Chapter 143

BCGosis and Hyperferritinemia Neslihan Edeer Karaca, Guzide Aksu, and Necil Kutukculer

An 8-month-old boy, born to non-consanguineous healthy parents, was admitted with fever. He received Bacille de Calmette-Guerin (BCG) vaccination at 2 months of age. He had bronchiolitis at 5 months. On admission, he weighted 6590 gr (3–10 percentile) and his height was 63 cm (3–10 percentile). He had left axillary lymphadenopathies of maximum 1.5∗1.5 cm in diameter and generalized microlymphadenopathies in cervical, submandibulary and inguinal regions. His liver was enlarged to 3 cm and the spleen was enlarged to 2 cm under the costal margin. Laboratory examinations revealed elevated WBC count, anemia and elevated acute phase reactants CRP: 25 mg/dL and ESR: 140 mm/h. Biochemical investigations were normal except for high ferritin (1160 μg/dL) level and inverted albumin/ globulin ratio (total protein 8.2 g/dl, albumin 2.8 g/dl). Viral and parasitic serologic examinations were negative, including serology for human immunodeficiency virus. Immunoglobulin levels were as follows: IgG 2640 mg/dL, IgM 145 mg/dL, IgA 20 mg/dL, and IgE 2,8 IU/mL. Quantiferon-TB test was negative. Abdominal ultrasonography showed multiple paraaortic lymphadenopathies in maximum 2 cm and hepatosplenomegaly. Bone marrow aspiration smear and biopsy were normal, ruling out hematologic malignancies. Liver biopsy showed granuloma formation composed of epithelioid histiocytes with giant cells. Histochemically multiple bacilli were present in the granulomas supporting the diagnosis of granulomatous hepatitis due to atypical mycobacterial infection (Fig. 143.1a). Cervical lymph node biopsy revealed granulomatous lymphadenitis and was positive for “Mycobacterium bovis-specific PCR”. He was diagnosed as BCG-osis with positive findings such as fever, generalized lymphadenopathies, hepatosplenomegaly, leukocytosis, anemia, elevated acute phase reactants and hypergammaglobulinemia.

N. E. Karaca (*) · G. Aksu · N. Kutukculer Ege University Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey © Springer Nature Switzerland AG 2019 N. Rezaei (ed.), Pediatric Immunology, https://doi.org/10.1007/978-3-030-21262-9_143

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Fig. 143.1  Acid-fast stained mycobacteria appeared as purple rods within hepatocytes in a Ziehl-Neelsen stain ((a) at 8 months of age and (b) at 2 years of age)

Q1. Which of the following conditions is associated with BCG vaccine -associated complications such as BCG-itis or BCG-osis? A. IgA deficiency B. Severe congenital neutropenia C. Chronic granulomatous disease D. X-linked lymphoproliferative disease Answer:  The correct answer is C. Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder resulting in genetic predisposition to infections by poorly pathogenic mycobacterial species or Mycobacterium tuberculosis in otherwise healthy children. Autosomal mutations in IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15 and IRF8 and X-linked mutations in nuclear facto kappa B (NF-kB) essential modulator (NEMO) and CYBB have been known to cause MSMD [1–3]. The BCG vaccine has a protective effect against meningitis and miliary tuberculosis in children [4]. The World Health Organization recommends that all infants in highly endemic countries receive a single dose of the BCG vaccine [4]. Adverse reactions to BCG in the general population are rare. The BCG-induced disease phenotypes are designated as local, regional, distant, or disseminated patterns [5]. Local BCG disease includes BCG injection site abscess of 10 mm or severe BCG scar ulceration. Regional disease includes enlargement, suppuration, or fistula formation of regional lymph nodes or lesions beyond the vaccination site, such as ipsilateral axillary lymph nodes. Distant disease is present when there is involvement of any site beyond regional lymph nodes, and disseminated disease is diagnosed when BCG is confirmed in more than one remote site or from at least one blood or bone marrow culture. The former two patterns were conventionally termed as BCG-itis and the latter two as BCG-osis. Our case was classified as definite disseminated disease on the basis of evidence of infection at 2 remote sites: i.e. liver and regional lymph node. Disseminated infection after BCG vaccination can be seen in patients with severe combined immunodeficiency (SCID), complete DiGeorge syndrome, chronic granulomatous disease (CGD) and IL-12/IFN-γ/IL-23 circuit defects [3, 6].

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Patient’s lymphocyte subsets were normal except inverted CD4+/CD8+ ratio, ruling out classic SCID. Quantitative determination of oxidative burst with “Phagoburst” kit, Glycotope, Biotechnology, was normal, excluding CGD. He was suspected to have a defect in IL-12/IFN-γ/IL-23 pathway. Treatment with isoniazide (INH), clarithromycin (CLR) and rifabutin (RIF), together with recombinant IFN-γ (0.05 mg/ m2, subcutaneously) was started. Due to severe disease phenotype, hematopoietic stem-cell transplantation (HSCT) was planned and screening for matched unrelated donor was started as he did not have HLA-identical family donor. During follow-up, he was noted to gain weight and began to walk and lymphoproliferation and hepatosplenomegaly regressed. Acute phase reactants remained high with gradually increasing ferritin levels in spite of good clinical condition. IgG levels were noted to decrease, whereas IgM was gradually increasing 8 months after first admission. The patient was admitted with darkening of the skin, fatigue and inability to walk at 2-years of age, while on antimycobacterial treatment. He had failure to thrive in the absence of chronic diarrhea. He had brownish skin color, coarse hair and hepatosplenomegaly. Laboratory examinations were listed in Table 143.1. Although the patient did not have fever, high ferritin levels and anemia prompted bone marrow aspiration biopsy to exclude hemophagocytic-lymphohistiocytosis was performed only to be found normal. Liver biopsy excluded iron deposition in hepatocytes by Prussian-blue stain ruling out hemochromatosis. Liver iron load was calculated as 0.75 mg/g/dry weight by MRI (hepatic iron