A Case of Aplastic Anemia and Colon Cancer With Underlying Spliceosome Mutation: Is It an Incidental Finding or a Novel Association?

Alternative splicing is an epigenetic mechanism that plays a role in the development and function of antigen-specific lymphocytes. One such is the zinc-finger-RNA-binding-motif-and-serine/arginine-rich-2 (ZRSR2), which is clinically implicated in myelodysplastic syndrome and leukemia. Here, we present a case of a young male with myriad autoimmune conditions and adenocarcinoma of the colon in the setting of ZRSR2 mutation. A 28-year-old male with common variable immunodeficiency disease, atopic dermatitis, autoimmune gastroenteropathy, inflammatory polyarthropathy, primary bone marrow failure, colon cancer, and family history of Lynch syndrome was admitted to our hospital for an acute flare of autoimmune enteropathy secondary to subtherapeutic tacrolimus levels. He initially developed pancytopenia at the age of 26 years. Workup for HIV, hepatitis, cytomegalovirus, human-herpesvirus 6, parvovirus was negative. Partial thromboplastin time (PTT), international normalized ratio (INR), d-dimer, ferritin, iron profile, antinuclear antibodies (ANA) screen was unremarkable. Direct, indirect, and super-combs antibodies were undetectable. Chromosomal study for Fanconi-related chromosomal breakage and telomerase gene panel was negative. Flow cytometry did not reveal an abnormal clone. Bone marrow biopsy showed markedly hypocellular marrow with reduced trilineage hematopoiesis and 1% blasts with normal cytogenetics, immunohistochemistry, fluorescence in situ hybridization (FISH), and negative for myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria (PNH). Cincinnati inherited children's bone marrow transplant (BMT) panel was negative. He was diagnosed with aplastic anemia and was treated with antithymocyte globulin, cyclosporine, prednisone, and currently tacrolimus. At the age of 26 years, he was diagnosed with colon cancer. Immunohistochemistry was positive for MLH1, but the confirmatory genetic testing for Lynch syndrome was negative. He underwent total proctocolectomy and ileostomy and is currently in remission. Next-generation sequencing of bone marrow revealed a germline homozygous ZRSR2 mutation.  ZRSR2 spliceosome mutations are more common in males as it's an X-linked gene. They are seen in myelodysplastic syndrome, leukemia, increased autoimmune phenomenon, and 35 cases of colon cancer associated with this mutation are reported. In the setting of aplastic anemia and lynch negative colon cancer, we suspect our patient could have aplastic anemia due to an autoimmune phenomenon, underlying common variable immunodeficiency disease (CVID), or the new ZRSR2 mutation could be playing a role. Further studies and research is warranted to determine its true association with the disease entities. The underlying contributing factor is ZRSR2 mutation.