Hereditary Hematologic Malignancies

Red blood cells (RBCs)

Erythrocyte

Low RBCs

Anemia

**fatigue, pain

High RBCs

Erythrocytosis

**flushing, headache, blurred vision

White blood cells (WBCs)

Leukocytes

Low WBCs

Leukopenia

**infections, mouth sores

High WBCs

Leukocytosis

**fatigue, hives, itching

Platelets (Plts)

Thrombocytes

Low Plts

Thrombocytopenia

**bleeding, easy bruising

High Plts

Thrombocytosis

**blood clots, stroke

Hematopoiesis

Leukemia

cancer cells are mainly in the bone marrow and blood

**acute vs chronic

**myeloid vs lymphoid

Acute

expedited diagnostic/treatment timeline

Chronic

has had leukemia for a while, monitoring, maybe no treatment yet

Lymphoma

cancer cells are mainly in the lymph nodes and other lymphatic tissue (blood can be involved)

**Hodgkin vs Non-Hodgkin

**b-cell vs t-cell

**indolent vs aggressive

Hodgkin lymphoma

Mr. Hodgkin is a young, cool guy, and you kinda want him, he's easier to treat (20s-30s or 70s-80s)

Non-Hodgkin lymphoma

That's not a name, that's something you should be seeing at older ages

MDS/AML average age of diagnosis

65

ALL average age of diagnosis

17

**ALL the children

HM workup

- peripheral blood sample (CBC)

- peripheral blood smear

- immunoglobulins (Ig)

- lymph node biopsy

- bone marrow aspiration and biopsy

- cytogenetics (i.e. karyotype, FISH, microarray)

- molecular genetics (site-specific testing, NGS panels/WES/WGS)

HM treatment

- chemotherapy (most types)

- radiation (lymphoma)

- HCT/HSCT/BMT

- immunotherapy

Important fhx questions for HMs

? HM dx and age

? abnormal blood counts

? easy bleeding and/or bruising

? recurrent or persistent infections

? immunodeficiency

? dermatologic findings

? congenital and/or developmental differences

? other tumors/cancers

? exposures

? consanguinity

Short telomeres cause...

ILD + pulmonary fibrosis

Increased risk for MDS/AML

What sample type should you use for a patient with a history of a HM?

Skin punch biopsy!

ANKRD26-related thrombocytopenia (thrombocytopenia 2)

Gene: ANKRD26 (mutations in 5' UTR)

Inheritance: AD

Characteristics: chronic thrombocytopenia, plt dysfunction, increased risk for MDS, AML, possibly other HMs

CEBPA-associated familial AML

Gene: CEBPA

Inheritance: AD

Characteristics: increased risk for early-onset AML (2y-50y)

RUNX1 familial platelet disorder with associated myeloid malignancies

Gene: RUNX1

Inheritance: AD

Characteristics: thrombocytopenia, plt dysfunction, eczema, psoriasis, increased risk for AML, MDS, ALL, possibly lymphomas

GATA2 deficiency

Gene: GATA2

Inheritance: AD (de novo)

Characteristics: cytopenias, immunodefiency, lung disease/infections, cutaneous and genital warts, lymphedema, hearing loss, blood clots, increased risk for BMF, MDS, AML, CMML in adolescence/young adulthood

Clonal hematopoiesis

an age-related condition where hematopoietic stem cells acquire somatic mutations, causing them to produce blood cells with identical genetic changes, often leading to expansion of these clones

**increased risk for HM

Somatic reversion/rescue

A process by which a disease-causing allele is altered to escape the effect of a germline variant, can muddy genetic testing

**if suspicious, use cultured fibroblasts for germline testing

Hereditary HMs

1) Myeloid malignancy predisposition

2) Inherited bone marrow failure syndromes

3) Inherited platelet disorders

4) Lymphoid malignancy predisposition

DDX41-associated familial MDS and AML

Gene:

Inheritance: AD

Characteristics: cytopenias (aplastic anemia), macrocytosis, increased risk for MDS, AML, and possibly solid tumors

**two DDX41 variants in myeloid HM is highly suggestive of an underlying germline variant

Most common acquired variant in DDX41

p.Arg525His (R535H)

ETV6-thrombocytopenia and predisposition to leukemia (thrombocytopenia 5)

Gene: ETV6

Inheritance: AD

Characteristics: thrombocytopenia, increased risk for HM (B-ALL) and possibly other solid tumors

If you see a patient with B-ALL, think...

ETV6!

Li-Fraumeni syndrome

Gene: TP53

Inheritance: AD (de novo)

Characteristics: increased risk for HM and a wide variety of solid tumors

If you see a patient with low-hypodiploid ALL, think...

TP53!

Other conditions associated with ALL

AT

Bloom syndrome

CMMRD

Diamond-Blackfan anemia

Down syndrome

Fanconi anemia

DDX41-associated familial MDS & AML

GATA2 deficiency

RUNX1-associated familial B-cell ALL

Telomere biology disorders

Other conditions associated with MDS/AML

Diamond-Blackfan anemia

Thrombocytopenia 5

Fanconi anemia

Li-Fraumeni syndrome

Telomere biology disorders

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and neoplasia (XMEN disease)

Gene: MAGT1

Inheritance: X-linked

Characteristics: chronic EBV infection, autoimmune cytopenias, cutaneous warts, mouth sores, sinopulmonary and ear infections, increased risk for EBV-associated lymphoproliferative disorders and lymphoms risk (lymphadenopathy, splenomegaly)

IBMF syndromes

1) Fanconi anemia

2) Shwachman-Diamond syndrome

3) Diamond-Blackfan anemia

4) telomere biology disorders

Telomere biology disorders

aka short telomere syndromes (STS) and dyskeratosis contenita

IMBF workup

Germline genetic testing

Functional laboratory studies (chromosomal breakage analysis, telomere length measurements, adenosine deaminase)

Fancona anemia (FA) characteristics

- bone marrow failure (pancytopenia)

- skeletal issues

- short stature

- microcephaly

- café au lait spots

- underdeveloped reproductive organs

- increased risk for AML

**usually diagnosed via chromosome breakage analysis

Genes associated with FA

AR: BRCA1, BRCA2, BRIP1, PALB2, RAD51C

AD: RAD51

X-linked: FANCB

FA clinical HM/CA timeline

5-15y: BMF

17-20s: HMs (AML, MDS)

Adulthood: solid tumor risk, especially oral cancers

Genes associated with telomere biology disorders

AR: CTC1, NHP2, NOP10, STN1, WRAP53

AR/AD: ACD, PARN, POT1, RTEL1, TERT

AD: NAF1, RPA1, TERC, TINF2, ZCCHC8

X-linked: DKC1