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Detailed genetic analyses revealed that patients presenting with single lineage or multilineage bone marrow failure (BMF) may have an underlying primary immunodeficiency (PID), according to a presentation at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress. Results of the study were presented by Maurizio Miano, MD, of the IRCCS Instituto Giannina Gaslini in Genoa, Italy.
Patients with congenital BMF can present with immunodeficiency, which may be misinterpreted as PID. Conversely, patients with PID may present with BMF. This overlap in disease phenotypes can delay the correct diagnosis and corresponding therapeutic approach.
“Genetic diagnosis can be helpful to administer targeted treatments and tailored conditioning regimens before stem cell transplantation,” said Dr Miano.
Therefore, the investigators conducted a retrospective evaluation of all patients with single/multilineage BMF treated at their center between 2009 and 2019 to identify the type and incidence of underlying molecular/genetic defects related to BMF and PID.
Testing varied depending on the available technology at the time. Prior to 2015, instances of congenital BMF including telomeropathies, congenital neutropenia, congenital amegakaryocytic thrombocytopenia, and Diamond-Blackfan anemia were assessed by Sanger sequencing. After 2015, BMF was evaluated with next-generation sequencing (NGS). For this study, all samples that tested negative before 2015 were re-analyzed with NGS. The diepoxybutane test was used to screen for Fanconi anemia (FA).
The NGS panel covered 146 genes related to congenital BMF, congenital neutropenia, autoimmune lymphoproliferative syndromes, and common variable immune deficiency PIDs. A second NGS panel of 315 genes included genes related to autoinflammatory diseases and complement diseases in addition to the 146 genes in the first panel.
In total, 97 patients were included in the study for single-lineage (30%) or multilineage (70%) BMF. The median age at diagnosis was 5 years (range, 0-32 years).
The analyses revealed that 54% of patients had an acquired BMF, 29% had a congenital BMF (12 FA, 5 dyskeratosis congenita, 6 severe congenital neutropenia, 3 Diamond-Blackfan anemia, and 2 congenital amegakaryocytic thrombocytopenia), and 17% had an underlying PID.
Of the 16 patients with PID, 9 had the overlapping BMF/PID phenotype showing multilineage failure. Half of the total cohort successfully underwent stem cell transplantation, 4 patients received immunosuppressive treatment, 2 patients received no treatment, and 2 patients died.
“Our study shows that about half of children with marrow failure may have a genetic background, and that PID can be the cause in a considerable number of cases. These findings strongly suggest that diagnostic work-ups of patients with monolinear or multilinear [bone marrow failure] should take into considerations such disorders that can be identified by large NGS panels including genes related to both groups of diseases or whole exome sequencing,” concluded Dr Miano.
Miano M, Dell’orso G, Lanciotti M, et al. Genetic screening of children with bone marrow failure: the role of primary immune deficiencies. Presented at: Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress; June 2020. Abstract S194.