Clinical Description
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, male predominance, and red blood cell macrocytosis. To date, more than 200 individuals have been identified with a confirmed or presumed germline disease-causing heterozygous variant in DDX41 [Polprasert et al 2015, Cardoso et al 2016, Lewinsohn et al 2016, Li et al 2016, Berger et al 2017, Kobayashi et al 2017, Diness et al 2018, Quesada et al 2019, Sébert et al 2019, Vairo et al 2019, Maierhofer et al 2020, Polprasert et al 2020, Bannon et al 2021, Choi et al 2021, Qu et al 2021, Zhang et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.
Myeloid Neoplasms
Individuals with DDX41-associated familial MDS/AML have an elevated lifetime risk of developing myeloid neoplasms; an exact risk estimate is not yet known. Myeloid malignancies including high-risk MDS and AML are the most common, with an average age of onset in the sixth decade (similar to the age of onset of sporadic MDS/AML) and a 3:1 male predominance [Polprasert et al 2015, Quesada et al 2019, Sébert et al 2019, Bannon et al 2021]. The MDS/AML phenotype usually features bone marrow hypocellularity with prominent erythroid dysplasia and a normal karyotype [Polprasert et al 2015, Lewinsohn et al 2016, Sébert et al 2019, Bannon et al 2021]. The MDS/AML tumor DNA will be identified to have a concomitant somatic DDX41 variant (in addition to the known germline variant) in 50%-88% of cases. The somatic variant is often a missense variant (p.Arg525His in the majority of cases) located in the C-terminal helicase domain. Additional somatic variants may be found in one or more myeloid malignancy-associated genes including ASXL1, TP53, CUX1, and genes that encode spliceosome factors [Polprasert et al 2015, Bannon et al 2021].
Myeloproliferative neoplasms, chronic myeloid leukemia, and chronic myelomonocytic leukemia with age of onset in late adulthood have also been reported [Lewinsohn et al 2016, Quesada et al 2019]. Individuals may develop more than one independent hematologic malignancy: two studies identified a prior history of a lymphoid or other hematologic malignancy in 9% of individuals with a confirmed or presumed germline DDX41 disease-causing variant at the time of a new MDS or AML diagnosis [Sébert et al 2019, Bannon et al 2021].
There are conflicting data regarding prognosis of MDS/AML in those with DDX41-associated familial MDS/AML compared to sporadic MDS/AML.
Lymphoid Neoplasms
Non-Hodgkin lymphoma (especially early-onset follicular lymphoma), Hodgkin lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have been reported in individuals with germline DDX41 pathogenic variants [Lewinsohn et al 2016, Sébert et al 2019, Polprasert et al 2020, Bannon et al 2021, Zhang et al 2021]. Age of onset is typically in adulthood. Three of 33 (9%) individuals with DDX41-related MDS/AML also had a personal history of a lymphoid malignancy [Sébert et al 2019].
Blood Count Abnormalities
Adult-onset single- or multiple-lineage cytopenias and/or red blood cell macrocytosis are common [Lewinsohn et al 2016, Quesada et al 2019, Sébert et al 2019, Bannon et al 2021]. Of these, some individuals will have prolonged, persistent blood count abnormalities; others will progress to have more severe or additional cytopenias or to an overt hematologic malignancy within months to a few years [Lewinsohn et al 2016, Quesada et al 2019, Sébert et al 2019, Bannon et al 2021, Zhang et al 2021]. Aplastic anemia has been reported in some individuals [Sébert et al 2019, Zhang et al 2021], a diagnosis that can be challenging to differentiate from low-risk MDS with a hypocellular marrow – a known MDS phenotype seen in DDX41-associated familial MDS/AML.
Other
Autoimmune disorders. To date, sarcoidosis (3 individuals), rheumatoid arthritis (1 individual), juvenile rheumatoid arthritis (1), systemic lupus erythematosus (1), Churg Strauss (1), and Grave's disease (1) have been reported in rare individuals with germline DDX41 pathogenic variants [Lewinsohn et al 2016, Diness et al 2018, Bannon et al 2021]. Whether the frequency of autoimmune disorders in individuals with germline DDX41 pathogenic variants is higher than would be expected in the general population remains to be definitively established.
Solid tumors. Solid tumors – most frequently prostate cancer, colorectal cancer, and melanoma – have been reported in individuals with germline DDX41 pathogenic variants. Six of 33 individuals (18%) with hematologic malignancies were noted to have had a prior diagnosis of a solid tumor, most frequently prostate cancer (3 individuals); however, individuals with solid tumor diagnoses alone (i.e., without hematologic manifestations) have also been reported [Lewinsohn et al 2016, Sébert et al 2019, Bannon et al 2021]. Whether the frequency of these solid tumors in individuals with germline DDX41 pathogenic variants is higher than would be expected in the general population remains to be definitively established.