Hereditary Hematologic Malignancies

pluripotent HSC

stem cells that can differentiate into many different heme cells

myeloid malignancies

acute myeloid leukemia

myelodysplastic syndromes

chronic myelogenous leukemia

myeloproliferative neoplasms

lymphoid malignancies

acute lymphoblastic leukemia

chronic lymphocytic leukemia

small lymphoblastic lymphoma

hodgkin lymphoma

non-hodgkin lymphoma

myeloid malignancies hereditary

malignancies with a larger hereditary component

bone marrow failure

reduced # of HSCs leading t low/absent myeloid and/or lymphoid progenitor cells

causes low blood cell counts in all lineages

15%

percentage of hereditary bone marrow failure

bone marrow failure syndromes

MDS

acquired aplastic anemia

fanconi anemia

schwachman-diamond syndrome

fanconi anemia features

bone marrow failure

short stature

abnormal skin pigmentation

limb defects

eye issues

genitourinary defects

fanconi anemia cancers

AML

skin

small cell carcinoma

fanconi anemia inheritance

primarily AR

RAD51: AD

FANCB: x linked

chromosome breakage assays

measures the rates & patterns of chromosomal breaks & rearrangements after exposure

detects fanconi anemia

allogenic stem cell transplant

stem cell transplant where stem cells are from another person

telomere biology disorders

bone marrow failure

dysplastic nails

pigmentation of the chest & neck

oral leukoplakia

pulmonary fibrosis

telomere biology disorder genes

DKC1, TINF2, TERT

telomere length testing

assesses the length of telomeres on chromosomes

used for telomere biology disorders

4-18%

percentage of individuals with AML, MDS, BMF with germline pathogenic variants

MDS guidelines

clinically suspected predisposition syndrome at any age

all patients <50 with MDS or AML

hypocellular MDS

aplastic anemia

MSL or AML and >/= 1 additional cancer

red flags for inherited heme malignancy

MDS, AML, aplastic anemia

thrombocytopenia

skin/nail anomalies

immunodeficiency

MDS inherited syndromes

familial platelet disorders

thrombocytopenia

AML inherited syndromes

SAMD9-related disorder

familial AML w/ CERPA or DDX41

GATA2 deficiency

AML w/ MRD4

ALL inherited syndromes

familial B-cell ALL

Li-fraumeni syndrome

germline SH2B3 or IKZF1

RUNX1

familial platelet disorder w/ myeloid malignancies gene

avg. age onset 33

DDX41

myeloid & lymphoid malignancy predisposition gene

male predominance

median age at diagnosis 60s

familial lymphoid malignancies

PAX5 pre-B cell ALL

Li fraumeni syndrome

SH2B3 associated ALL (AR)

ETV6 associated ALL

CMMRD (AR)

lymphoma

relatively common hematopoietic malignancy

primarily multifactorial