Diagnostic Criteria

Suggestive Findings

DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) should be suspected in individuals with the following clinical, laboratory, or family history findings.

Clinical findings

• Myeloid neoplasms. Most common types are MDS, AML, therapy-related myeloid neoplasms, with age of onset typically in the sixth decade.

Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms.

• Lymphoid neoplasms (less common). Types include non-Hodgkin lymphoma (follicular lymphoma most frequent), Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, with age of onset typically in adulthood.

• Aplastic anemia (rare)

Laboratory findings

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"

Differential Diagnosis

Table 2.

Genes of Interest in the Differential Diagnosis of DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia

Gene(s) /GeneticMechanism | Disorder | MOI | Characteristic Features

Overlapping w/DDX41-assoc familial MDS/AML | Not observed in DDX41-assoc familial MDS/AML

14q32 duplication | 14q32 duplication-associated familial myeloproliferative neoplasms (OMIM 616604)1 | AD | ET/PV/PMF (w/frequent progression to MDS/AML); MDS/AML/CMML | Predominantly myeloproliferative neoplasms w/progression to MDS/AML, often w/complex karyotype

ACD

CTC1

DKC1

NAF1

NHP2

NOP10

PARN

RTEL1

TERC

TERT

TINF2

WRAP53

ZCCHC8

| Dyskeratosis congenita other telomere biology disorders (e.g., pulmonary fibrosis) | ADARXL | Myeloid neoplasms; solid tumors | Dysplastic nails, lacy reticular pigmentation of upper...

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"

Management Guidelines

No clinical practice guidelines for DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DDX41-associated familial MDS/AML, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"

Clinical Guidance

Avoid (if possible) stem cell transplant from related donors who have the familial DDX41 pathogenic variant, as donor cell-derived leukemia has been reported in individuals after allogeneic hematopoietic stem cell transplant using donors with pathogenic germline DDX41 variants . Avoid smoking, chemical exposure, and unnecessary radiation, as these may increase the risk of developing hematologic malignancy.

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"

Therapies Under Investigation

Responsiveness to lenalidomide for DDX41-associated familial MDS/AML has been observed . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"

Surveillance Guidelines

No evidence-based guidelines on the type of testing or frequency of surveillance for DDX41-associated familial MDS/AML have been published. The table below reflects published expert opinion-based recommendations.

Table 5.

Recommended Surveillance for Individuals with DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia

System/Concern | Evaluation | Frequency

Hematologic

| CBC w/differential | Every 6-12 mos or more frequently as clinically indicated1

Clinical exam for constitutional signs symptoms of MDS/AML (e.g., fatigue, infections, bleeding, skin changes)1 | Annually or more frequently as clinically indicated

Bone marrow biopsy aspirate, cytogenetics | Consider in healthy persons w/normal blood counts on an individual basis.

AML = acute myeloid leukemia; CBC = complete blood count; MDS = myelodysplastic syndrome

1.

Source: GeneReviews — "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia"