Bone marrow neoplastic

Bone marrow - neoplastic myeloid

Myeloid neoplasms with germline predisposition without a constitutional disorder affecting multiple organ systems

with DDX41 mutation



Last staff update: 22 January 2024 (update in progress)

Copyright: 2020-2024, PathologyOutlines.com, Inc.

PubMed Search: DDX41 myeloid neoplasm

Nourhan Ibrahim, M.D.
Brenda Mai, M.D.
Page views in 2023: 31
Page views in 2024 to date: 156
Cite this page: Ibrahim N, Al-Jumaili Z, Armstrong J, Mai B. with DDX41 mutation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneomyeloidDDX41.html. Accessed March 29th, 2024.
Definition / general
  • Autosomal dominant trait caused by pathogenic germline mutational variants in the DDX41 gene, increasing the risk of hematolymphoid neoplasms
Essential features
  • Pathogenic germline mutational variant on chromosome 5q35.3
  • Autosomal dominant inheritance
  • Familial myeloproliferative / lymphoproliferative neoplasms
Terminology
  • DEAD box helicase 41
ICD coding
  • ICD-10: C96.7 - other specified malignant neoplasms of lymphoid, hematopoietic and related tissue
Epidemiology
  • Germline DDX41 pathogenic variants are the most common cause for genetic predisposition to myeloid neoplasms and are identified in 1 - 4% of patients with myeloid neoplasms (Cancer Cell 2015;27:658, Blood 2019;134:1441, Am J Hematol 2019;94:757)
  • Lifelong risk of developing myeloid neoplasms from a pathogenic or likely pathogenic DDX41 variant is ~50%, starting at 40 years of age (Blood 2023;141:534)
  • Men with the gene variant have nearly double the risk of developing a myeloid neoplasm compared with female carriers (Blood 2022;140:716)
  • Certain DDX41 germline variants are more common in certain populations (e.g., p.Ala500Cysfs*9 in Japanese / Korean and p.D140Gfs*2 in those of Northern European descent) (Blood 2023;141:1544)
Sites
  • Bone marrow / peripheral blood
  • Lymph nodes (less common)
Pathophysiology
  • Precise mechanism by which germline DDX41 variants drive hematopoietic malignancies is still unknown
  • DDX41 gene is located on chromosome 5q35.3
  • DDX41 is expressed on hematopoietic cells and it encodes an ATP dependent RNA helicase that participates in RNA metabolism (Cancer Cell 2015;27:658)
  • Germline DDX41 variants are typically heterozygous and include frameshift, nonsense or splice site mutations whereas somatic mutations are usually missense heterozygous variants that affect the helicase 2 ATP binding domain (Blood 2016;127:1017)
  • DDX41 is found both in the cytoplasm and nucleus, where it plays a role in messenger RNA splicing, ribosomal RNA processing or small nucleolar RNA processing (Blood 2023;141:1544)
  • Disruption of the DDX41 protein contributes to inflammation and tumorigenesis (Blood 2023;141:1544)
Etiology
  • Germline DDX41 pathogenic mutations are passed on from a parent to child in an autosomal dominant inheritance pattern
  • Pathogenic variant is usually heterozygous
Diagrams / tables

Images hosted on other servers:
Proposed mechanisms for DDX41 involvement

Proposed mechanisms for DDX41 involvement

Clinical features
  • Individuals with a pathogenic DDX41 variant have an increased lifelong risk (~50%) of developing a myeloid neoplasm, including clonal cytopenia of undetermined significance (CCUS), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), myelodysplastic / myeloproliferative neoplasm (MDS / MPN) and acute myeloid leukemia (AML) starting at age 40 (Blood 2023;141:534)
  • Germline DDX41 variants are found in 3 - 5% in MDS, 5 - 9% in secondary AML, 1 - 2% in MDS / MPNs and < 0.5% in MPNs (Blood 2023;141:534)
  • Aplastic anemia may occur but is rare
  • Some patients may develop a lymphoid neoplasm or a plasma cell neoplasm; however, this is much less common than myeloid neoplasms and includes follicular lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma and acute lymphoblastic leukemia (Blood 2016;127:1017)
Diagnosis
  • WHO 5th edition diagnostic category: myeloid neoplasms associated with germline predisposition
  • WHO 5th edition essential diagnostic criteria: detection of a pathogenic or likely pathogenic DDX41 variant
  • WHO 5th edition desirable diagnostic criteria: detection of pathogenic or likely pathogenic germline DDX41 variant at a variant allele frequency consistent with germline status from DNA derived from cultured skin fibroblasts or via segregation in other family members
  • Reference: Am J Hematol 2023;98:1780, Am J Hematol 2023;98:1780
Laboratory
Prognostic factors
  • Prognostic impact of germline DDX41 variants is unclear
  • Truncating germline DDX41 variants in patients who develop MDS are associated with faster transformation to AML compared with patients with nontruncating germline variants but no difference in overall survival is observed between these groups (Blood 2023;141:534)
Case reports
  • 9 year old boy presented with essential thrombocythemia-like features with a pathogenic germline variant in DDX41, JAK2 and a constitutional inv(7)(q11.2q22) (J Pediatr Hematol Oncol 2023;45:e609)
  • 48 year old man with Ph+ B cell lymphoblastic leukemia with biallelic DDX41 mutations (BMC Med Genomics 2022;15:46)
  • 62 year old man with myelodysplastic syndrome and DDX41 mutation treated successfully with lenalidomide (Am J Hematol 2020;95:227)
  • 70 year old man with an adult onset myeloid neoplasm with excess blasts without dysplasia and germline missense DDX41 variant (Leuk Lymphoma 2019;60:1337)
  • Caucasian family with inherited MDS / AML with 2 germline mutations in the DDX41 gene (Haematologica 2016;101:e228)
Treatment
  • No evidence based guidelines on the treatment for DDX41 associated familial MDS / AML have been published and patients are generally treated with standard neoplasm specific therapy
  • Patients with MDS associated with germline DDX41 pathogenic variants tend to have better response to hypomethylating agents and better outcomes compared to those with wild type DDX41 (Blood 2023;141:534)
  • Allogeneic hematopoietic stem cell transplant evaluation early in the course of hematologic malignancy may be appropriate based on the age of the individual, malignancy and health status
Microscopic (histologic) description
  • Hematolymphoid neoplasms arising in individuals with a DDX41 germline variant do not have distinctive morphologic features
  • Patients with a DDX41 variant have an increased likelihood of bone marrow hypocellularity and erythroid dysplasia (Am J Hematol 2019;94:757)
  • DDX41 mutation can lead to ineffective hematopoiesis resulting in cytopenia and macrocytosis in the peripheral blood (Front Oncol 2022:12:992340)
  • It is reported that patients with DDX41 variants can have persistent higher blast count in myelodysplastic syndrome or AML; among MDS subtypes, refractory anemia with excess blasts is the most frequent (Leuk Lymphoma 2019;60:1337)
Microscopic (histologic) images

Contributed by Jacob Armstrong, M.D.
Hypocellular bone marrow core

Hypocellular bone marrow core

Hyperchromatic megakaryocytes

Hyperchromatic megakaryocytes

Hypercellular bone marrow core

Hypercellular bone marrow core

Marrow with AML

Marrow with AML

CD34 with ~10% blasts

CD34 with ~10% blasts

CD61 with megakaryocyte atypia

CD61 with megakaryocyte atypia


Aspirate with increased blasts

Aspirate with increased blasts

nRBC with irregular nuclei

nRBC with irregular nuclei

nRBC with nuclear budding

nRBC with nuclear budding

nRBC with multinucleation

nRBC with multinucleation

Hypolobated megakaryocytes

Hypolobated megakaryocytes

Ring sideroblasts

Ring sideroblasts

Cytology description
  • Granulocytes
    • Can show dysplastic features (hypogranular or hyposegmented forms)
    • Increased blasts and immature myeloid precursors can be present
  • Erythrocytes
    • Can have dysplastic features including irregular nuclear contours, nuclear budding, binucleation, multinucleation, nuclear dyssynchrony, megaloblastoid changes and basophilic stippling
  • Megakaryocytes
    • Can have dysplastic features including large variation in sizes, small forms (micromegakaryocytes), hypolobated nuclei, widely spaced nuclei, hypersegmented (staghorn) nuclei and nuclear hyperchromasia
  • Blasts can be increased
  • Iron: ring sideroblasts can be present
  • Reference: GeneReviews: DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia [Accessed 19 October 2023]
Peripheral smear description
  • Red blood cells (RBCs)
    • Normal RBC count, anemia or erythrocytosis can be present
    • Anemia including microcytic, normocytic or macrocytic
      • Macrocytosis is the most common finding
    • Anisopoikilocytosis, including teardrop cells (if there is myelofibrosis), etc.
    • Nucleated red blood cells (nRBC) can be present
  • White blood cells (WBCs)
    • Normal WBC count, leukocytosis or leukopenia can be present
    • Granulocytes can show dysplastic features (hypogranular or hyposegmented forms)
    • Circulating blasts and immature myeloid precursors can be present
  • Platelets
    • Normal platelet count, thrombocytopenia or thrombocytosis can be present
    • Morphology of platelets is usually unremarkable
  • Reference: GeneReviews: DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia [Accessed 19 October 2023]
Peripheral smear images

Contributed by Jacob Armstrong, M.D.
Macrocytic anemia

Macrocytic anemia

Circulating blasts and nRBC

Circulating blasts and nRBC

Positive stains
  • There are no diagnostic stains for DDX41 mutation; helpful stains include
    • CD34: enumeration of CD34 positive blasts
    • CD117: enumeration of CD117 positive blasts and erythroid precursors
    • TdT: positive on some blasts
    • CD123: positive on some blasts
    • CD42b: highlights megakaryocytes
    • CD61: highlights megakaryocytes
    • Factor VIII: highlights megakaryocytes
    • CD15: highlights granulocytes
    • MPO: highlights the myeloid lineage
    • E-cadherin: highlights the erythroid lineage
    • CD71: highlights the erythroid lineage
    • Glycophorin A: highlights the erythroid lineage
    • CD4: highlights monocytes and a subset of T cells
    • CD68: highlights monocytes
    • Reticulin: highlights reticulin fibrosis
    • Trichrome: highlights collagen fibrosis
  • Reference: Am J Hematol 2023;98:1780
Flow cytometry description
  • No reported distinctive flow cytometry immunophenotypic pattern; however, individuals with DDX41 mutation can have an increased blast population or granulocytes with decreased side scatter as a reflection of hypogranularity
Flow cytometry images

Contributed by Zubaidah Al-Jumaili, M.D.
CD45 versus side scatter CD45 versus side scatter

CD45 versus side scatter

CD34 versus CD117 CD34 versus CD123

CD34 versus CD123

Molecular / cytogenetics description
  • Cytogenetics findings
    • DDX41 pathogenic variants are not associated with any karyotype abnormalities; while patients with DDX41 variants can have karyotype abnormalities, these changes are independent of the DDX41 mutation (Am J Hematol 2019;94:757)
  • Molecular findings
    • Deleterious germline DDX41 variants confer increased risk for myeloid neoplasms with an estimated prevalence of 1 - 4% among MNs
    • DDX41 can be mutated in the germline or in a somatic fashion
      • Germline mutations of DDX41 have been reported to predispose patients to somatic mutations and subsequent MDS or AML
      • ~50% of patients with germline mutations also harbor somatic mutations in the other allele of DDX41
    • The most frequent DDX41 mutation identified is a frameshift duplication causing a premature stop codon (p.D140Gfs*2); however, missense and splice variants are also described
    • The most frequent co-occurring somatic mutations involve ASXL1, CUX1, TP53, DNMT3A and TET2 and among these, CUX1 mutations are preferentially observed in DDX41 mutated cases compared with wild type ones (Am J Hematol 2019;94:757)
Molecular / cytogenetics images

Images hosted on other servers:
Distribution of DDX41 mutations along the gene

Distribution of DDX41 mutations along the gene

Germline and somatic DDX41 mutations

Germline and somatic DDX41 mutations

Deleterious DDX41 germline variants

Deleterious DDX41 germline variants

Videos

What is the clinical impact of DDX41 mutations in myeloid neoplasms?

Germline predisposition to myeloid malignancies

Sample pathology report
  • Bone marrow, biopsy:
    • Hypocellular (30%) bone marrow with dyserythropoiesis and ~10% blasts (see comment)
    • Comment: Bone marrow aspirate smears show erythroid dysplasia and a mild increase in blasts, comprising ~10% of the total nucleated cells on the aspirate smear. The bone marrow core biopsy and clot section are hypocellular for age with increased scattered blasts marked by CD34 immunostain. Flow cytometric analysis shows increased abnormal myeloblasts that comprise about 10.2% of total events with an atypical immunophenotype (CD2+, CD13+, CD33+, CD34+, CD38+, CD117+, CD123+, MPO+). These findings are compatible with a myelodysplastic neoplasm with increased blasts. NGS studies show a DDX41 mutation. This is consistent with a myeloid neoplasm associated with germline predisposition, more specifically, myelodysplastic neoplasm with increased blasts with DDX41 mutation.
Differential diagnosis
  • Myeloid neoplasms associated with a DDX41 pathogenic variant:
    • Clonal cytopenias of undetermined significance (CCUS):
      • Detection of 1 or more somatic mutations with variant allele frequency (VAF) ≥ 2% (≥ 4% for X linked gene mutations in men) in DNA from blood or bone marrow cells involving genes listed in table #32521 of the clonal hematopoiesis section of the WHO 5th edition or clonal chromosomal abnormalities in myeloid cells
      • 1 or more otherwise unexplained cytopenias that persist for > 4 months
      • Absence of diagnostic criteria for defined myeloid neoplasms on bone marrow examination
    • Myelodysplastic neoplasm (MDS):
      • Cytopenia in at least 1 hematopoietic lineage: Hb < 13 g/dL in men and < 12 g/dL in women for anemia, absolute neutrophil count < 1.8 x 109/L for leukopenia and platelets < 150 x 109/L for thrombocytopenia
      • Please see diagnostic criteria for MDS with defining genetic abnormalities or morphologically defined MDS
        • Defining genetic abnormalities include
          • MDS with low blasts and 5q deletion (MDS-5q)
          • MDS with low blasts and SF3B1 mutation (MDS-SF3B1)
          • MDS with biallelic TP53 inactivation (MDS-biTP53)
        • Morphologically defined MDS includes
          • MDS with low blasts (MDS-LB)
          • MDS, hypoplastic (MDS-h)
          • MDS with increased blasts (MDS-IB)
          • MDS with fibrosis (MDS-f)
    • Myelodysplastic neoplasm (MDS) / myeloproliferative neoplasm (MPN):
      • Please see diagnostic criteria for MDS / MPN entities
        • Chronic myelomonocytic leukemia
        • Myelodysplastic / myeloproliferative neoplasm with neutrophilia
        • Myelodysplastic / myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis
        • Myelodysplastic / myeloproliferative neoplasm, NOS
    • Myeloproliferative neoplasm (MPN):
      • Please see diagnostic criteria for MPN entities
        • Chronic myeloid leukemia
        • Chronic neutrophilic leukemia
        • Chronic eosinophilic leukemia
        • Polycythemia vera
        • Essential thrombocythemia
        • Primary myelofibrosis
        • Juvenile myelomonocytic leukemia
        • Myeloproliferative neoplasm, NOS
    • Acute myeloid leukemia (AML):
      • Blasts comprising at least 20% or AML defining genetic features including t(8;21), t(15;17) or t(16;16)/inv(16)
    • Myeloid neoplasm postcytotoxic therapy:
      • Myeloid neoplasm meeting diagnostic criteria of any myelodysplastic neoplasm, myelodysplastic / myeloproliferative neoplasm or acute myeloid leukemia
      • History of prior exposure to cytotoxic therapy or large field radiation therapy for an unrelated disorder
      • Not meeting diagnostic criteria of myeloproliferative neoplasms
  • Other germline variants that cause predisposition to myeloid neoplasms:
  • Other syndromes that cause predisposition to myeloid neoplasms:
Board review style question #1

A 46 year old man presents with macrocytic anemia and thrombocytopenia. Bone marrow aspirate smears show the findings above. The bone marrow is hypercellular for age with hyperchromatic megakaryocytes. Cytogenetics findings reveal a 20q deletion and next genome sequencing shows a DDX41 pathogenic variant. The patient has a brother with similar findings. Which of the following is the diagnosis?

  1. Acute myeloid leukemia
  2. Chronic myeloid leukemia
  3. Chronic myelomonocytic leukemia
  4. Myeloid neoplasm postcytotoxic therapy
  5. Myeloid neoplasms associated with germline predisposition
Board review style answer #1
E. Myeloid neoplasms associated with germline predisposition. Myeloid neoplasms associated with germline predisposition include any myeloid neoplasms that are diagnosed in a patient with a DDX41 variant. The photo demonstrates several erythroids with binucleation, which is consistent with erythroid dysplasia and suggestive of MDS. The bicytopenia, erythroid dysplasia and hypercellular marrow along with a description of dysplastic megakaryocytes are consistent with MDS. Answer A is incorrect because the image does not display an increase in blasts. Answer B is incorrect because the image does not show myeloid hyperplasia with increased immature granulocytes; the cytogenetic and molecular findings also do not show a t(9;22) or BCR::ABL1. Answer C is incorrect because the image does not show myeloid hyperplasia with increased granulocytes and monocytes. Answer D is incorrect because there is no evidence in the question stem that the patient has received cytotoxic therapy.

Comment Here

Reference: with DDX41 mutation
Board review style question #2
Which of the following red blood cell (RBC) findings are most commonly seen in myeloid neoplasms with DDX41 mutation?

  1. Macrocytic anemia
  2. Microcytic anemia
  3. Normocytic anemia
  4. Normocytic normochromic red blood cells
Board review style answer #2
A. Macrocytic anemia. Macrocytic anemia is the most common finding in myeloid neoplasms with DDX41 mutation. Answer B is incorrect because microcytic anemia is typically seen in iron deficiency anemia or thalassemia and not myeloid neoplasms. Answer D is incorrect because while normocytic red blood cells (without anemia) can be seen in myeloid neoplasms, DDX41 is typically associated with macrocytic anemia due to marrow disruption of normal erythroipoiesis. Answer C is incorrect because normocytic anemia is the second typical finding in the red blood cells in myeloid neoplasms with DDX41 mutation.

Comment Here

Reference: with DDX41 mutation
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