Myeloid Neoplasms with Germline Predisposition Flashcards
What is the definition of
Myeloid neoplasms with germline predisoposition ?
- increasely recognized entity that has clinical implications for patient management
- autosomal dominant
- other known conditions including bone marrow failure disorders and the telomere biology disorders
- other germline predisposition syndromes (discussed elsewhere0
- Down Syndrome
- Neurofibromatosis
- Noonan syndrome
What are the general categories of
myeloid neoplasms associated with germline predisposition
(MNAGP) ?
- MNAGP without a pre-existing disorder or organ dysfunction
- MNAGP with pre-existing platelet disorders
- MNAGP and other organ dysfunction
What disease are seen in MNAGP without
pre-existing platelet disorder or organ dysfunction ?
- AML with germline CEBPA mutation
- Myeloid neoplasms with germline DDX41 mutation
What disease are seen in MNAGP with
pre-existing platelet disorders?
- myeloid neoplasms with RUNX1 mutation
- myeloid neoplasms with germline ANKRD26 mutation
- myeloid neoplasms with germline ETV6 mutation
What diseases are seen in MNAGP
with other organ dysfunction ?
- Myeloid neoplasms with germline GATA2 mutation
- Myeloid neoplasms with bone marrow failure syndromes
- Myeloid neoplasms associated with telomere biology disorders
- JMML associated with NF, Noon syndrome and Noonan syndrome like disorders
- Myeloid neoplasms associated with Down Syndrome
What is the epidemiology of
MNAGP ?
- uknown incidence but considered to be rare
- may present in childhood or early adulthood
- underlying germline mutations are the cause of the disease
- IMP: some myeloid neoplasms develop due to additional molecular or cytogenetic alterations
What are the clinical features of MNAGP ?
- no specific clinical presentation for the whole group
- rather clinical is specific to the gene altered associated syndrome
- a good detailed history, including bleeding history, must be performed to help facilitate diagnosis
p. 124 chart (review)
What is the genetic event for
AML with germline CEBPA mutation ?
- this is a MNAGP without a pre-existing platelet or organ dysfunction
- inheritance of a single copy of mutated CEBPA (near complete penetrance for AML)
- encodes a granulocytic differentiation factor
- found on chromosome 19q13.1
- this is a biallelic mutation
- one inherited
- one somatic mutation of CEBPA occurs
- Note:
- acquired GATA2 mutations are also common in this setting
What is important to recognize about
AML with biallelic CEBPA mutations ?
- good prognosis AML
- WHO defined AML
- should prompt investigation into germline mutations
What is the epidemiology and clinical of AML
with billelic CEBPA mutation ?
- typically present in children or young adults
- AML is the primary presenting feature
- no preceding blood count abnormalities
What are the morphologic and immunophenotypic
features characteristic of AML with biallelic CEBPA mutation ?
- predominance of AML without maturation
- can have Auer rods
- frequent aberrant CD7 expression on the blasts
- normal karyotype
What is the definition of Myeloid neoplasms with
germline DDX41 mutation ?
- recently described autosomal dominant familial MDS/AML
- gene is on chromosome 5
- mutation is often biallelic with one being germline
- high penetrance
What is the epidemiology of
Myeloid neoplasms with germline DDX41 mutation ?
- true incidence unknown but appears to have a long latency period
- first manifest in patients in their 60s
- patients develop high grade myeloid neoplasms (MDS or AML)
- other described entities
- CML, CMML, Hodgkin and non-Hodgkin lymphomas
What is the clinical presentation of
myeloid neoplasms with germline DDX41 mutation ?
- usually present with leukopenia
- with or without other cytopenias
- hypocellular bone marrow with prominent erythroid dyasplasia
- often get erythroid leukemia
- generally poor prognosis
- may respond to lenalidomide
What is the definition of myeloid neoplasms with
RUNX1 mutation ?
- part of the group with pre-existing platelet disorders
- familial platelet disorder with predisposition to MDS/AML at a young age
- Autosomal dominant
- germline monoallelic mutation in RUNX1 on chromosome 21q22
- prevalence of this has not been determined
What is the clinical presntation for
myeloid neoplasms with RUNX1 ?
- variable clinical presentation even in the same family
- medain age of onset is 33
- anticipation seems to occur
- prognosis is difficult to ascertain
- mild to moderate bleeding tendency
- usually evident from childhood
- platelet counts are normal to mildly reduced with normal platelet morphology
- variable degrees of platelet dysfunction
- impaired platelet aggregation with collagen and epinephrine
- dense granule storage pool deficiency
What are the common malignancies that
RUNX1 germline develop ?
- MDS and AML
- Other neoplasms seen:
- CMML
- T-ALL
- rarely B cell neoplasms: Hairy cell leukemia
What are the genetics of RUNX1 germline neoplasms ?
- RUNX1 mutations can include deletions, insertions, frameshift etc
- progression to AML may likely need additional mutations
- which can explain variable penetrance and anticipation
- second RUNX1 mutations are a common hit but no required
What is the definition of myeloid neoplasms with
germline ANKRD26 mutation ?
- associated with pre-existing platelet disorders
- germline ANKRD26 = Thrombocytopenia 2
- located on chromosome 10
- Autosomal dominant
- increased risk of developing MDS/AML
- mutations disrupt the assembly of RUNX1 and FLI1
- leads to decreased pro-platelet formation by megakaryocytes
