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
What is the clinical presentation of
patients with ANKRD26 mutation ?
- 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
What is the morphology seen on biopsy
in ANKRD26 mutated myeloid neoplasms ?
- 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
What neoplasms are patients with ANKRD26 mutations
prone to developing ?
- 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
What is the definition of myeloid neoplasms with
germline ETV6 mutation ?
- 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
What malignancies have been
described in germline ETV6 mutations ?
- MDS
- AML
- CMML
- B-ALL
- plasma cell neoplasms
- Colorectal adenocarcinoma
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
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
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
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.
What is a frequently associated
cytogenetic aberration with germline GATA2?
- often have a monosomy 7
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
What are the most common cytogenetic
abnormalities associated with GATA2 germline?
- monosomy 7
- trisomy 8
What are the clinical outcomes of patients
with GATA2 germline mutations ?
- poor prognosis
- improved with stem cell transplantation
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.
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%)
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
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.
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%
What are the phenotypic findings
in severe congenital neutropenia ?
- HAX1
- neurodevelopmental issues
- G6PC3
- cardiac and other
How is severe congenital neutropenia
diagnosed ?
- gene sequencing of relevant mutations
What are the genetic alterations of
Shwachman Diamond Syndrome?
- AR:
- SBDS
- they can go on to develop MDS, AML, and ALL (5-24%)
What are the phenotypic findings of
Shwachman-Diamond Syndrome ?
- preceding isolated neutropenia
- pancreatic insufficiency
- short stature
- skeletal abnormalities
- including metaphyseal dysostosis
How is Shwachman diamond syndrome diagnosed ?
- gene sequencing for SBDS mutations
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
What are the phenotypic findings in
Diamond-Blackfan Anemia ?
- small stature
- congenital anomalies (craniofacial, cardiac, skeletal, genitourinary)
What is the testing for Diamond-Blackfan Anemia ?
- Screening:
- elevated erythrocyte adenosine deaminase
- elevateated Hemoglobin F
- Confirmation
- gene sequencing for relavent mutations
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%)
What are the phenotypic features of
dyskeratosis congenita ?
- nail dystrophy and abnormal skin pigmentation
- oral leukoplakia
- pulmonary fibrosis
- hepatic fibrosis
- squamous cell carcinoma
How is testing performed for
Dyskeratosis congenita?
- telomere length measurement by flow-FISH
- if abnormal then gene sequencing for relavent mutations
