We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency.
Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/μL day 42 after infusion of CAR-T cells or filgrastim support to reach that number.
We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.
One dose of filgrastim 300 μg was administered subcutaneously on day 6 in response to the pancytopenia, after which the platelet, hemoglobin, and WBC values stabilized for a day and then generally declined.
The pancytopenia was diagnosed as an adverse effect of nivolumab; filgrastim (75 μg/day), steroid-pulse therapy (intravenous methylprednisolone: 500 mg/day), and subsequently intravenous prednisolone (50 mg/day) were administered.
In those patients who survive the initial phase of poisoning, filgrastim (granulocyte colony-stimulating factor) offers an effective method of treating pancytopenia and preventing overwhelming septicemia.
A 50-year-old man with large granular lymphocytic leukemia (CD3+, CD8+) complicated by severe pancytopenia and life-threatening infections refractory to therapy with prednisone, methotrexate, cyclosporine, and G-CSF is described.
We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of <i>MECOM</i> sequencing in the diagnostic workup of congenital bone marrow failure.
We also found mutations in genes seldom reported in inherited BMF (IBMF), such as <i>SAMD9</i> and <i>SAMD9L</i> (N = 16 of the 86 patients, 18.6%), <i>MECOM/EVI1</i> (N = 6, 7.0%), and <i>ERCC6L2</i> (N = 7, 8.1%), each of which was associated with a distinct natural history; <i>SAMD9</i> and <i>SAMD9L</i> patients often experienced transient aplasia and monosomy 7, whereas <i>MECOM</i> patients presented early-onset severe aplastic anemia, and <i>ERCC6L2</i> patients, mild pancytopenia with myelodysplasia.
We report for the first time a constitutional deletion encompassing the EVI1 and MDS1 genes in a human, and argue that the deletion causes congenital bone marrow failure in this patient.
However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations.
Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype.