Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry

Abstract

Background: Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications.

Design and methods: Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii.

Results: One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia.

Conclusions: This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.

Figure 1.

Cumulative incidence by age of adverse events and adverse event rates in IS-IBMFR with Fanconi anemia. (A) Cumulative incidence of the first adverse event, severe bone marrow failure as defined by Rosenberg et al., leukemia, and solid tumor (ST), using a competing risk analysis. (B) Annual cause-specific hazard rates of severe BMF, leukemia, myelodysplastic syndrome (MDS), and ST. The shaded areas represent the 95% point-wise confidence intervals.

Figure 2.

Cumulative incidence by age of development of cancer in IS-IBMFR patients. FA: Fanconi anemia; SCN: severe congenital neutropenia; CAMT: congenital amegakaryocytic thrombocytopenia. The shaded areas represent the 95% point-wise confidence intervals.

Figure 3.

Cumulative survival of IS-IBMFR patients calculated using the Kaplan-Meier method. FA: Fanconi anemia (n=66); SCN: severe congenital neutropenia (n=21); DBA: Diamond-Blackfan anemia (n=18); CAMT: congenital amegakaryocytic thrombocytopenia (n=8). The shaded areas represent the 95% point-wise confidence intervals.