Myeloid Neoplasms with Germline Predisposition Flashcards
(48 cards)
1
Q
What is the definition of
Myeloid neoplasms with germline predisoposition ?
A
- 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
2
Q
What are the general categories of
myeloid neoplasms associated with germline predisposition
(MNAGP) ?
A
- MNAGP without a pre-existing disorder or organ dysfunction
- MNAGP with pre-existing platelet disorders
- MNAGP and other organ dysfunction
3
Q
What disease are seen in MNAGP without
pre-existing platelet disorder or organ dysfunction ?
A
- AML with germline CEBPA mutation
- Myeloid neoplasms with germline DDX41 mutation
4
Q
What disease are seen in MNAGP with
pre-existing platelet disorders?
A
- myeloid neoplasms with RUNX1 mutation
- myeloid neoplasms with germline ANKRD26 mutation
- myeloid neoplasms with germline ETV6 mutation
5
Q
What diseases are seen in MNAGP
with other organ dysfunction ?
A
- 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
6
Q
What is the epidemiology of
MNAGP ?
A
- 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
7
Q
What are the clinical features of MNAGP ?
A
- 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)
8
Q
What is the genetic event for
AML with germline CEBPA mutation ?
A
- 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
9
Q
What is important to recognize about
AML with biallelic CEBPA mutations ?
A
- good prognosis AML
- WHO defined AML
- should prompt investigation into germline mutations
10
Q
What is the epidemiology and clinical of AML
with billelic CEBPA mutation ?
A
- typically present in children or young adults
- AML is the primary presenting feature
- no preceding blood count abnormalities
11
Q
What are the morphologic and immunophenotypic
features characteristic of AML with biallelic CEBPA mutation ?
A
- predominance of AML without maturation
- can have Auer rods
- frequent aberrant CD7 expression on the blasts
- normal karyotype
12
Q
What is the definition of Myeloid neoplasms with
germline DDX41 mutation ?
A
- recently described autosomal dominant familial MDS/AML
- gene is on chromosome 5
- mutation is often biallelic with one being germline
- high penetrance
13
Q
What is the epidemiology of
Myeloid neoplasms with germline DDX41 mutation ?
A
- 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
14
Q
What is the clinical presentation of
myeloid neoplasms with germline DDX41 mutation ?
A
- 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
15
Q
What is the definition of myeloid neoplasms with
RUNX1 mutation ?
A
- 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
16
Q
What is the clinical presntation for
myeloid neoplasms with RUNX1 ?
A
- 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
17
Q
What are the common malignancies that
RUNX1 germline develop ?
A
- MDS and AML
- Other neoplasms seen:
- CMML
- T-ALL
- rarely B cell neoplasms: Hairy cell leukemia
18
Q
What are the genetics of RUNX1 germline neoplasms ?
A
- 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
19
Q
What is the definition of myeloid neoplasms with
germline ANKRD26 mutation ?
A
- 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
20
Q
What is the clinical presentation of
patients with ANKRD26 mutation ?
A
- incidence is uknown
- platelet count is variable but moderate thrombocytopenia is the norm
- many have glycoprotein Ia and alpha granule deficiency
- platelet aggregation studies are usually normal
- thrombopoietin levels are oftene elevated
21
Q
What is the morphology seen on biopsy
in ANKRD26 mutated myeloid neoplasms ?
A
- dysmgakaryopoiesis can be seen
- they are increased in number and often small with hyposegmented nuclei or two nuclei
- includes micromegakaryocytes
- small number of patients have
- increased hemoglobin and WBC counts
22
Q
What neoplasms are patients with ANKRD26 mutations
prone to developing ?
A
- MDS and AML are 30 times more likely to develop in these patients
- most cases are AML
- rare reports of other neoplasms:
- CML
- CMML
- CLL
23
Q
What is the definition of myeloid neoplasms with
germline ETV6 mutation ?
A
- associated with pre-existing platelet disorders
- autosomal dominant
- familial thrombocytopenia and hematological neoplasms
- normal sized platelets
- mild to moderate bleeding tendency
- occasionally present in infancy
- can have small, hyposegmented megas and mild dyserythropoiesis
24
Q
What malignancies have been
described in germline ETV6 mutations ?
A
- MDS
- AML
- CMML
- B-ALL
- plasma cell neoplasms
- Colorectal adenocarcinoma
25
What syndromes were originally described
with GATA 2 mutations ?
* MonoMAC Syndrome
* Dendritic cell, monocyte, B and NK lymphoid deficiency with vulnerability to viral infections
* Familial MDS/AML
* Emberger Syndrome
GATA2 germline mutations are seen in myeloid neoplasms with associated other organ dysfunction
Note:
* GATA2 has also been rarely described with congenital neutropenia and aplastic anemia
26
What is MonoMAC syndrome and Emberger syndrome
associated with GATA2 germline mutation ?
* MonoMAC syndrome
* monocytopenia and non-TB infection
* Emberger syndrome
* primary lymphedema
* warts
* predisposition to MDS/AML
27
What is the function of GATA2 ?
* zinc-finger transcription factor regulating hematopoiesis, autoimmunity, and inflammatory developmental processes
* mutation is monoallelic, results in haploinsufficiency
* diagnosed by full gene sequencing and large rearrangement testing
28
What is the clinical presentation of
GATA2 germline mutations ?
* very heterogeneous group
* small subset develop AML directly but many patients develop MDS with evolution to AML or CMML
* median age of development is 29 years
* history of immunodeficiency with lymphedema may be seen but some patients just present with MDS/AML.
29
What is a frequently associated
cytogenetic aberration with germline GATA2?
* often have a monosomy 7
30
What are the characteristic morphological
features of GATA2 germline predisposition ?
* bone marrow hypocellularity and multilineage dysplasia
* most prominent in megakaryocytic lineages
* includes micromegas and megas with peripheral separated
* increased reticulin fibrosis
* abnormal maturation patterns of granulocytes and monocytes by flow cytometry
* reduced bone marrow NK and B cells
* plasma cells often aberrantly express CD56
* Increased T-LGL populations are common
31
What are the most common cytogenetic
abnormalities associated with GATA2 germline?
* monosomy 7
* trisomy 8
32
What are the clinical outcomes of patients
with GATA2 germline mutations ?
* poor prognosis
* improved with stem cell transplantation
33
What defined syndromes have a predisposition
to the development of Myeloid Neoplasms ?
* Fanconi anemia
* Severe congenital neutropenia
* Shwachman-Diamond Syndrome
* Diamond-Blackfan anemia
* Telomere biology disorders
* dyskeratosis congenita syndromes due to TERC and TERT mutation
Note: the phenotypes are quite variable and may be absent in some patients. Therefore, diagnosis can be delayed even until adulthood.
34
What are some of the genes important
in Fanconi anemia ?
* there are many autosomal recessive genes involved in F.A.
* ex: FANCA, FANCC
* **_the single X linked recessive gene: FANCB_**
* patients develop MDS and AML (~10%)
35
What are the phenotypic findings
of Fanconi anemia ?
* bone marrow failure
* low birth weight
* short stature
* radial anomolies
* congenital heart disease
* micropthlamia
* ear anomalies and deafness
* renal malformations
* hypogonadism
* cafe au lait spots
* solid tumors
36
How is Fanconi anemia diagnosed ?
* Screening:
* chromosomal breakage analysis
* Confirmation:
* gene sequencing for relevant mutations
IMP: 25% of cases do not have classic phenotypic findings and thus diagnosis may be delayed.
37
What are some of the genes important in
severe congenital neutropenia ?
* AD:
* ELANE, CSF3R, GFI1
* AR:
* HAX1, G6PC3
* XLR:
* WAS
* they develop MDS/AML in 20-40%
38
What are the phenotypic findings
in severe congenital neutropenia ?
* HAX1
* neurodevelopmental issues
* G6PC3
* cardiac and other
39
How is severe congenital neutropenia
diagnosed ?
* gene sequencing of relevant mutations
40
What are the genetic alterations of
Shwachman Diamond Syndrome?
* AR:
* SBDS
* they can go on to develop MDS, AML, and ALL (5-24%)
41
What are the phenotypic findings of
Shwachman-Diamond Syndrome ?
* preceding isolated neutropenia
* pancreatic insufficiency
* short stature
* skeletal abnormalities
* including metaphyseal dysostosis
42
How is Shwachman diamond syndrome diagnosed ?
* gene sequencing for SBDS mutations
43
What are the genetic alterations in Diamond-Blackfan anemia ?
* AD:
* many mutations
* XLR:
* GATA1
* develop MDS, AML and ALL (5%)
* increased risk of colorectal cancer in late 30-40s
44
What are the phenotypic findings in
Diamond-Blackfan Anemia ?
* small stature
* congenital anomalies (craniofacial, cardiac, skeletal, genitourinary)
45
What is the testing for Diamond-Blackfan Anemia ?
* Screening:
* elevated erythrocyte adenosine deaminase
* elevateated Hemoglobin F
* Confirmation
* gene sequencing for relavent mutations
46
What are the genetic alterations in
Dyskeratosis congenita and related syndromes ?
* XLR:
* DKC1
* AD:
* TERT, TERC, TINF2, RTEL1
* AR:
* NOP10, NHP2, WRAp53 and others
* develop MDS and AML (2-30%)
47
What are the phenotypic features of
dyskeratosis congenita ?
* nail dystrophy and abnormal skin pigmentation
* oral leukoplakia
* pulmonary fibrosis
* hepatic fibrosis
* squamous cell carcinoma
48
How is testing performed for
Dyskeratosis congenita?
* telomere length measurement by flow-FISH
* if abnormal then gene sequencing for relavent mutations
