Page 82 - Haematologica Vol. 107 - September 2022

ARTICLE - Bone Marrow Failure
Syndromes predisposing to leukemia are a major cause of
inherited cytopenias in children
Oded Gilad,1,2 Orly Dgany,3 Sharon Noy-Lotan,3 Tanya Krasnov,3 Joanne Yacobovich,1,2 Ron Rabinowicz,1,2 Tracie Goldberg,1 Amir A. Kuperman,4,5 Abed Abu-Quider,6 Hagit Miskin,7,8 Noa Kapelushnik,2,9 Noa Mandel-Shorer,10,11 Shai Shimony,2,12,13 Dan Harlev,14 Tal Ben-Ami,8,15 Etai Adam,16 Carina Levin,11, 17 Shraga Aviner,18 Ronit Elhasid,2,19 Sivan Berger-Achituv,2,19 Lilach Chaitman-Yerushalmi,20 Yona Kodman,1 Nino Oniashvilli,1 Michal Hameiri-Grosman,1 Shai Izraeli,1,2 Hannah Tamary1,2,3 and Orna Steinberg-Shemer1,2,3
1Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel; 4Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya, Israel; 5Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; 6Pediatric Hematology, Soroka University Medical Center, Ben-Gurion University, Beer Sheva, Israel; 7Pediatric Hematology Unit, Shaare Zedek Medical Center, Jerusalem, Israel; 8Faculty of Medicine, Hebrew University, Jerusalem, Israel; 9Goldschleger Eye Institute, Sheba Medical Center, Tel Hashomer, Israel; 10Department of Pediatric Hematology-Oncology, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, Haifa, Israel; 11Rappaport Faculty of Medicine, Technion-Institute of Technology, Haifa, Israel; 12Rabin Medical Center, Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Petach-Tikva, Israel; 13Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 14Pediatric Hematology-Oncology Department, Hadassah University Medical Center, Jerusalem, Israel; 15Pediatric Hematology Unit, Kaplan Medical Center, Rehovot, Israel; 16Pediatric Hematology- Oncology Department, Sheba Medical Center, Tel Hashomer, Israel; 17Pediatric Hematology Unit and Research Laboratory, Emek Medical Center, Afula, Israel; 18Department of Pediatrics, Barzilai University Medical Center, Ashkelon, affiliated to Ben Gurion University, Beer-Sheva, Israel, 19Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center Tel Aviv, Israel and 20Genoox, Health Care Technology, Tel Aviv, Israel.
Abstract
Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias pre- disposing to leukemia require a timely and accurate diagnosis to ensure appropriate medical management, including adequate monitoring and stem cell transplantation prior to the development of leukemia. We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. The study comprises children with persistent cytopenias, myelodysplastic syndrome, aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used Sanger se- quencing of commonly mutated genes and a custom-made targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias; the minority subsequently underwent whole exome sequencing. In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, nine (19.1%) had inherited thrombocytopenia predisposing to leukemia, and three each (6.4%) had predisposition to myelodysplastic syndrome or congenital neutropenia. Twelve patients had cytopenias with no known leuke- mia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia. In sum- mary, almost one third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.
differential diagnosis, including acquired and inherited
disorders.1-2 Among inherited disorders, predisposition to Prolonged cytopenias are a non-specific sign with a wide leukemia has recently emerged as an important clinical
Haematologica | 107 September 2022
Correspondence: H. Tamary htamary@tauex.tau.ac.il
Received: Accepted: Prepublished:
September 30, 2021. March 10, 2022. March 17, 2022.
https://doi.org/10.3324/haematol.2021.280116
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
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