ICUS to ICU: A Case of Germline DDX41 Mutation in a Patient with Idiopathic Cytopenia of Undetermined Significance (ICUS)

Abstract

Genetic testing for both somatic and germline mutations is a crucial component of the modern work up of cytopenia, myeloid neoplasms, and bone marrow failure syndromes. However, the specific genes tested in each clinical scenario are continually evolving, making standards for genetic testing a moving target. Germline mutation of the DDX41 gene is associated with familial acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but its role in idiopathic cytopenia of undetermined significance (ICUS) is less clear. We present the case of a 65-year-old male with a history of rheumatoid arthritis (RA) found to have ICUS with a germline DDX41 mutation.  The patient’s cytopenia was long standing, present at least 3 years prior to initiation of immunosuppression for his RA. Two months after his initial hematologic evaluation, the patient was admitted to the ICU for neutropenic enterocolitis. The patient was severely neutropenic and required a right hemicolectomy. Subsequent work-up revealed a pathogenic germline DDX41 mutation. Repeat bone marrow biopsy 8 months later was consistent with MDS/AML as defined by 2022 International Consensus Classification Guidelines. This patient, asymptomatic for years, went through an ICU admission and emergent surgery before his germline DDX41 mutation was discovered. Expanded guidelines regarding somatic and germline genetic testing will likely prove helpful in delineating the etiology of ICUS and initiating early management in the future.