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Bone Marrow Failure
Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1825-1834
Orna Steinberg-Shemer,1,2,3* Tracie A. Goldberg,1* Joanne Yacobovich,1,2 Carina Levin,4,5 Ariel Koren,4,5 Shoshana Revel-Vilk,6 Tal Ben-Ami,7
Amir A. Kuperman,8,9 Vered Shkalim Zemer,1,2 Amos Toren,2,10
Joseph Kapelushnik,11 Ayelet Ben-Barak,12 Hagit Miskin,6 Tanya Krasnov,3 Sharon Noy-Lotan,3 Orly Dgany3 and Hannah Tamary1,2,3
1Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; 3Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva; 4Pediatric Hematology Unit, Emek Medical Center, Afula; 5The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa; 6Pediatric Hematology/Oncology Unit, Shaare Zedek Medical Center, Jerusalem, affiliated with Hadassah- Hebrew University Medical School, Jerusalem; 7Pediatric Hematology Unit, Kaplan Medical Center, Rehovot; 8Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya; 9Azrieli Faculty of Medicine, Bar-Ilan University, Safed; 10Department of Pediatric Hemato-Oncology, Children's Hospital (Edmond and Lily), Sheba Medical Center, Tel-Hashomer; 11Pediatric Hematology, Soroka University Medical Center, Ben-Gurion University, Beer Sheva and 12Pediatric Hematology-Oncology Department, Rambam Medical Center, Haifa, Israel
*OS-S and TAG contributed equally as co-first authors.
ABSTRACT
Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congeni- tal anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hun- dred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no signifi- cant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and fol- low-up programs.
Introduction
Fanconi Anemia (FA), an inherited bone marrow failure (BMF) syndrome, results from defects in the DNA repair pathway, leading to chromosomal instability. The disease is rare with an estimated prevalence of 1:130,0001 but tends to be higher in certain communities due to founder mutations, especially those with a high rate of
Correspondence:
HANNAH TAMARY
htamary@post.tau.ac.il
ORNA STEINBERG-SHEMER
orna.steinberg@gmail.com
Received: March 27, 2019. Accepted: September 25, 2019. Pre-published: September 26, 2019.
doi:10.3324/haematol.2019.222877
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