title: Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients.
abstract: Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life-threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live-births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR-CGD) and 32 (38%) with X-linked recessive inheritance (XLR-CGD). Consanguinity was detected in 64% of AR-CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR-CGD and 13 in AR-CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long-term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28-36, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Pediatric Hematology Clinic and the Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Baruch
authors.initials: B
authors.lastname: Wolach
authors.affiliation: Pediatric Hematology Clinic and the Laboratory for Leukocyte Function, Meir Medical Center, Kfar Saba Israel, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Gavrieli
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: de Boer
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: van Leeuwen
authors.affiliation: Department of Pediatric Hemato-Oncology, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Berger-Achituv
authors.affiliation: Immunology Service, Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Stauber
authors.affiliation: Meyer Children's Hospital and Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Josef
authors.initials: J
authors.lastname: Ben Ari
authors.affiliation: Division of Allergy & Immunology, Ha'Emek Medical Center, Afula, Israel and Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Menachem
authors.initials: M
authors.lastname: Rottem
authors.affiliation: Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Schlesinger
authors.affiliation: Pediatric Infectious Diseases Unit, Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Grisaru-Soen
authors.affiliation: Ambulatory Pediatrics, Nablus, Palestinian Authority.
authors.forename: Omar
authors.initials: O
authors.lastname: Abuzaitoun
authors.affiliation: Allergy and Immunology Unit, Schneider Children's Medical Center, Tel Aviv, Israel.
authors.forename: Nufar
authors.initials: N
authors.lastname: Marcus
authors.affiliation: Allergy and Immunology Unit, Schneider Children's Medical Center, Tel Aviv, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Zion Garty
authors.affiliation: Immunology Clinic, Soroka Medical Center, Beer Sheva, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Broides
authors.affiliation: Immunology Clinic, Soroka Medical Center, Beer Sheva, Israel.
authors.forename: Jakov
authors.initials: J
authors.lastname: Levy
authors.affiliation: Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepansky
authors.affiliation: Meyer Children's Hospital and Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.affiliation: Immunology Service, Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
authors.affiliation: Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001424:Bacterial Infections / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007557:Israel; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009181:Mycoses / Q000382:microbiology; D019255:NADPH Oxidases / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055815:Young Adult
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases