DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia

Clinical characteristics: DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) is characterized by an increased risk of myeloid neoplasms, lymphoid neoplasms, adult-onset single- or multiple-lineage cytopenias (including aplastic anemia), and red blood cell macrocytosis. The most common myeloid neoplasms include MDS, AML, and therapy-related myeloid neoplasms. Chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms are less common. Lymphoid neoplasms include non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.

Diagnosis/testing: The diagnosis of DDX41-associated familial MDS/AML is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in DDX41 identified by molecular genetic testing.

Management: Treatment: Standard neoplasm-specific therapy; allogeneic hematopoietic stem cell transplant evaluation early in the course of hematologic malignancy if appropriate based on the age of the individual, malignancy, and health status – including identification of potential related donors for genetic counseling and genotyping.

Surveillance: Complete blood count with differential every six to 12 months or more frequently as clinically indicated; annual clinical examination for constitutional signs and symptoms of MDS/AML (e.g., fatigue, infections, bleeding, and skin changes). Consider bone marrow biopsy and aspirate with cytogenetics.

Genetic counseling: DDX41-associated familial MDS/AML is inherited in an autosomal dominant manner. To date, all reported individuals diagnosed with DDX41-associated familial MDS/AML whose parents have undergone molecular genetic testing have the disorder as the result of a pathogenic variant inherited from a parent. The heterozygous parent may or may not have developed a hematologic malignancy. If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. Once the DDX41 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.