Frequency and Natural History of Inherited Bone Marrow Failure Syndromes: The Israeli Inherited Bone Marrow Failure Registry
Authors: Tamary Hannah , Nishri Daniella , Yacobovich Joanne , Zilber Rama , Aviner Shraga , Stepensky Polina , Ravel Shoshana S Vilk- , Bitan Menachem , Kaplinsky Chaim , Barak Ayelet Ben , Kapelusnik Joseph , Koren Ariel , Levin Carina , Yaniv Isaac , Rosenberg Philip S , Alter Blanche P. 
Published: April 2020

Abstract
Inherited bone marrow failures syndromes (IBMFS) are rare genetic disorders usually characterized by congenital anomalies, development of bone marrow failure and a tendency to develop malignant diseases. Although single disease registries for Fanconi anemia (FA), Diamond-Blackfan Anemia (DBA), Severe Congenital Neutropenia (SCN) and Dyskeratois Congenita (DC) have been established the true incidence of many of the IBMFS is still unknown. To investigate the prevalence of each of the IBMFS and to the types and frequencies of complications we set up a retrospective national registry of these disorders in Israel. We reviewed charts of 127 patients with IBMFS diagnosed between 1964 and 2005. This represents the majority of such patients in the country. Consanguinity was recorded in 50 (40%) patients. Median time since diagnosis was 6 years (range: 1 month-39 years). Genetic analysis was available in 60 (47%) patients. The number of patients within each disease category is presented in the Table. The majority of patients who succumbed to their disease had FA. Of the 29 patients who developed malignancies (hematological and solid) the majority 23 (79%) had FA. All of the 6 patients who developed solid tumors had FA. The solid tumors were squamous cell carcinoma of head and neck, esophagus, cervix and vulva.
Table: Israeli Inherited Bone Marrow Failure Cohort - Diagnosis, Complications and Survival
No. of pts. FA DBA SCN CAMT DC SDS TAR NOS All Total (%) 66 (52) 18 (14) 21 (16.5) 8 (6) 6 (5) 3 (2) 3 (2) 2 (1.5) 127 (100) Per 106 people 5.3 2.6 2.1 1.1 0.86 0.43 0.29 Deceased (%) 24 (36) - 6 (29) - 2 (33) 1 (33) - - 33 (26) Molecular diagnosis (%) 34 (51) 6 (33) 7 (33) 8 (100) 4 (67) 1 (33) - - 60 (47) MDS/AML/ALL (%) 19 (29) - 4 (19) 2 (25) - - - - 25 (20) Solid tumor (%) 6 (9) - - - - - - - 6 (5)
CAMT, Congenital Amegakaryocytic Thrombocytopenia; SDS-Shwachman-Diamond Syndrome; TAR, Thrombocytopenia Absent Radii; NOS-not otherwise specified. This is the largest population-based study which has examined the relative frequency of each of the IBMFS. In this cohort, FA was by far the most common form of an IBMFS (52% of pts), followed by DBA (16.5%) and SCN (14%), while CAMT, DC, SDS and TAR were far less common. These findings agree with the frequencies of FA, DBA and SCN reported by individual disease registries, and contrast with the results from the Canadian inherited marrow failure registry (Pediatr Blood Cancer47:918, 2006), where among a smaller number (39) of patients with an IBMFS the frequencies of FA, SDS, DBA and SCN were similar (12% each). One caveat is that the Israeli cohort has a large proportion of consanguineous families, which differs from most cohorts in other countries. The number of undiagnosed patients with IBMFS in our study was very small. SDS and DC are either rare in our region or under-diagnosed. The implementation of new diagnostic tests will help to resolve this issue. These data provide a rational basis for longitudinal surveillance and prevention of complications in the severe forms of IBMFS.