Bone marrow neoplastic
Bone marrow - neoplastic myeloid
Myeloid neoplasms with germline predisposition and other organ dysfunction
with GATA2 mutation


Minor changes: 4 June 2021

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PubMed Search: Myeloid neoplasms with germline GATA2 mutation

Zhenya Tang, M.D., Ph.D.
Courtney D. DiNardo, M.D.
Page views in 2020: 31
Page views in 2021 to date: 147
Cite this page: Tang Z, DiNardo CD. with GATA2 mutation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticGATA2.html. Accessed July 27th, 2021.
Definition / general
  • Classified as one of the myeloid neoplasms with germline predisposition and other organ dysfunction in the revised 2016 WHO classification (Blood 2016;127:2391)
  • Now known to underlie several syndromes: MonoMAC syndrome, dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and Emberger syndrome
Essential features
  • Counts for the cause of 7 - 15% of primary myelodysplastic syndrome cases in children and adolescents and for approximately 37% of myeloid neoplasms with monosomy 7 (-7) or other forms of 7q- / -7 in adolescents and young adults
  • Differentiating somatic from germline GATA2 mutations is necessary
  • Genetic counseling of family members and timely screening of donors for presence of predisposition germline mutations are necessary prior to hematopoietic stem cell transplant for optimal patient outcomes
  • Skin fibroblasts are the gold standard for obtaining germline DNA in patients with myeloid neoplasms
Terminology
  • Myeloid neoplasms with germline GATA2 mutation
  • Familial myeloid neoplasms
  • Familial myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML)
ICD coding
  • Coding not available for this entity, however:
    • ICD-O: 984-993 - Myeloid leukemias
    • ICD-10: C92.A0 - Acute myeloid leukemia with multilineage dysplasia, not having achieved remission
Epidemiology
Sites
  • Myeloid neoplasms mainly involve the peripheral blood and bone marrow
  • Many other organs other than bone marrow (e.g. ear, lung, heart, joints, skin, blood vessels and immune system) can also be involved, especially if a germline GATA2 mutation associated syndrome exists (Blood 2014;123:809)
Pathophysiology
  • Resulting in loss of function of the mutated allele, GATA2 haploinsufficiency, then affecting proliferation and maintenance of hematopoietic stem cells (Hematol Oncol Clin North Am 2018;32:713)
Etiology
  • Autosomal dominant
Clinical features
Diagnosis
  • Same as each type of myeloid neoplasm (e.g. myelodysplastic syndrome, myeloproliferative neoplasm or acute myeloid leukemia) (Blood 2016;127:2391)
Prognostic factors
Case reports
Treatment
  • Same as each type of myeloid neoplasm (e.g. myelodysplastic syndrome, myeloproliferative neoplasm or acute myeloid leukemia) (Blood 2016;127:2391)
  • Hematopoietic stem cell transplantation; however, genetic screening of related donors to avoid reintroduction of germline mutation with predisposition is necessary
Clinical images

Images hosted on other servers:

Recalcitrant periungual warts

Microscopic (histologic) images
Virtual slides

Images hosted on other servers:

Alveolar proteinosis in lung tissue, GATA mutation positive

H&E staining

PAS staining

Peripheral smear images

Contributed by Wei Wang, M.D., Ph.D.

Pancytopenia in MDS

Megakaryocytic dysplasia in MDS

Positive stains
  • Variable, depending on the type and stages of myeloid neoplasm but not specifically associated with the underlying germline GATA2 mutation
Negative stains
  • Variable, depending on the type and stages of myeloid neoplasm but not specifically associated with the underlying germline GATA2 mutation
Flow cytometry description
  • Variable, depending on the type and stages of myeloid neoplasm but not specifically associated with the underlying germline GATA2 mutation; for example, in childhood myelodysplastic syndrome with germline GATA2 mutation, characteristic immunophenotyping changes include but are not limited to granulocytopenia, monocytopenia, decreased B cells and NK cells, presence of CD56+ plasma cells, etc.
Flow cytometry images

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Flow cytometry study of peripheral blood

Molecular / cytogenetics description
  • Molecular findings:
    • Mutation of various types (missense, nonsense, indels, etc.), involving exon(s) or intron(s) of GATA2 gene
  • Cytogenetic findings:
    • -7 / 7q-, +8, +21 or other aberration(s)
  • Next generation sequencing (NGS): in 10 - 15% cases, large deletions or mutations in intronic region of GATA2 gene may be involved and they can be missed with standard gene panel based NGS; therefore, NGS based whole exome (WES) or even whole genome (WGS) sequencing can be applicable to identify rare mutation(s) or those located within an intron (Leuk Lymphoma 2020;61:3010, JCO Precis Oncol 2019;3:PO.18.00301)
  • Sanger sequencing, especially for known mutation(s)
  • Conventional cytogenetic analysis or FISH, with focus on monosomy 7 or 7q abnormality, trisomy 8 and trisomy 21
  • Note: somatic GATA2 mutations reportedly coexist with other germline mutations (e.g. ASXL1, CEBPA) or other acquired drive mutations in myeloid neoplasm cases; differentiating somatic from germline GATA2 mutations is necessary
  • Additional references: Blood 2014;123:809, Best Pract Res Clin Haematol 2020;33:101197
Molecular / cytogenetics images

Contributed by Zhenya Tang, M.D., Ph.D.

Abnormal karyotype with r(7)

Sample pathology report
  • Bone marrow biopsy, right posterior iliac crest:
    • Gross measurement: 1.2 cm in aggregate. Quality: limited, subcortical. Cellularity: near empty marrow with only 2 small foci of cellular areas with erythroid predominant. Megakaryocytes: present. Infiltrate: no increase in immature cells.
  • Bone marrow clot:
    • Quality: adequate, 10 - 20% cellularity, morphology similar to biopsy.
  • Bone marrow smear / touch preparations:
    • Quality: adequate. Granulocytes: decreased with maturation and dysplasia. Erythrocytes: relatively increased with maturation and occasional dyserythropoiesis. Megakaryocytes: rare. Lymphocytes: not increased. Plasma cells: not increased. Blasts: not increased.
  • Stains of bone marrow smears, clots and biopsy:
    • Iron: slightly increased, no ringed sideroblasts. Reticulin / trichrome: inadequate for reticulin and trichrome stain evaluation. MPO: positive in scattered cells, decreased. CD71 / glycophorin A: highlight increased erythroids. CD61: highlights few scattered megakaryocytes.
  • Bone marrow diagnosis:
    • Hypocellular marrow with erythroid predominance and granulocytic dysplasia, 2% blasts, morphologically and immunophenotypically consistent with myelodysplastic syndrome (MDS). An underlying congenital condition should be considered (see comment).
    • Comment: 23 year old man with a history of recurrent skin infections and warts, CBC with mild pancytopenia and marrow biopsy showed hypocellularity. Concurrent flow cytometry analysis demonstrated aberrant myeloblasts, lack of hematogones, virtual absence of monocytes, minimal NK cells and only 1.1% of B cells. In addition, a tiny atypical T cells population is also detected, CD2+, CD3+, CD5 dim, CD4-, CD8 partial, CD56+, CD57 bright. The overall picture is highly suspicious for a congenital GATA2 mutation. Correlation with pending NGS result will be helpful for confirmation. Correlation with pending ancillary study results is recommended for complete evaluation.
Differential diagnosis
  • Germline versus somatic GATA2 mutation
  • Syndromic versus nonsyndromic germline GATA2 mutation
  • Reference: Blood 2014;123:809
Board review style question #1
What is the gold standard to obtain reliable germline DNA in a patient with a hematologic malignancy?

  1. Bone marrow biopsy and cell culture
  2. Buccal swabs and saliva
  3. Nails or hair
  4. Peripheral blood and cell culture
  5. Skin biopsy and cell culture
Board review style answer #1
E. Skin biopsy and cell culture. Genetic testing of cultured skin fibroblasts is the gold standard for obtaining germline DNA in patients with hematologic malignancies. DNA from nails or hair can be also used if skin biopsy and cell culture are not feasible. Peripheral blood and bone marrow can be affected by myeloid neoplasm or other hematological malignancies; they should be used cautiously as a source of germline DNA. Buccal swabs and saliva are often contaminated with blood cells and they should also be cautiously used as resource of germline DNA (2016 WHO classification).

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Reference: Myeloid neoplasms with germline predisposition and other organ dysfunction with GATA2 mutation
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