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ASPHO Lectures 2021 > Bone Marrow Failure > Flashcards

Bone Marrow Failure Flashcards

1
Q

Examples of Inherited Bone Marrow Failure Syndromes (IBMFS)?

A
  • Fanconi Anemia
  • Dyskeratosis Congenita
  • Diamond-Blackfan Anemia
  • Scwachman-Diamond Syndrome
  • Congenital Amegakaryocytic Thrombocytopenia
  • Thrombocytopenia Absent Radii
  • Severe Congenital Neutropenia
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2
Q

Etiologies of acquired aplastic anemia?

A
  • Medications
  • Chemicals
  • Toxins
  • Viral infection
  • PNH
  • Idiopathic (immune)
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3
Q

Fanconi Anemia - cancer predispositions?

A
  • MDS/AML
  • Squamous cell carcinoma (oral, vaginal vulvar)
  • Brain tumours
  • Wilms tumours
  • Other solid tumours
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4
Q

Fanconi Anemia - most common congenital anomalies? Classic one?

A
  • Skin - cafe au lait or hypopigmentation
  • Short stature
  • Classic: Upper limb - hypoplastic or absent radii (and absent thumb)
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5
Q

Fanconi anemia - diagnosis? If high clinical suspicion, but equivocal test? Role of mutation analysis? Other less commonly used test?

A
  • Peripheral blood karyotype with and without exposure of patient cells to breakage inducing agent: either diepoxybutane (DEB) or mitomycin C (MMC)
  • If high clinical suspicion and equivocal, repeat on cultured skin fibroblasts
  • Mutation analysis confirmatory, but not diagnostic test
  • Less common: flow cytometry clastogen induced G2/M arrest
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6
Q

Why can chromosomal breakage studies be falsely normal on PB? What to do?

A
  • Significant proportion have hematopoietic somatic mosaicism - molecular event that has corrected one mutated allele in bone marrow stem cell –> acquired heterozygosity in the blood cells
  • Do skin fibroblst culture to demonstrate sensitivity to DNA-damaging agent
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7
Q

Inheritance of Fanconi anemia?

A

-Autosomal recessive EXCEPT for FANC-B (X-linked recessive)

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8
Q

What do the Fanconi genes code for?

A

Nuclear protein complex that repairs DNA

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9
Q

Most common genetic abnormalities for Fanconi anemia?

A
  • FANC-A; 16q24.3 (60-70%0

- FANC-C; 9q22.3 (10-15%)

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10
Q

Fanconi anemia: Examples of mutation or complementation group predicting clinical course?

A
  • FANC-A: later onset of BMF
  • FANC-C & G: More severe course
  • FANC-B/D1: Mutatios in BRCA2 gene; very early onset of MDS/AML
  • FANC-D1, N: Wilm’s tumour medulloblastoma
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11
Q

Fanconi anemia: medications to slow count decline?

A
  • Oxymethalone (androgen)

- Danazol - less virilizing for females

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12
Q

Side effects of androgens? Monitoring requirements?

A
  • Virilization
  • Growth spurt –>premature epiphyseal closure - adult short stature
  • Hyperactivity/behavioural changes
  • Cholestatic jaundice or transaminitis
  • Hepatic adenoma, hepatocellular carcinoma
  • Piliosis hepatis (“blood lakes”)
  • Hypertension

-Follow LFTS and hepatic US

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13
Q

Risk of malignancy in Fanconi Anemia?

A
  • 1000X greater than normal

- 30% by adulthood

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14
Q

Incidence of leukemia in Fanconi anemia? Solid tumour? Liver tumour? Female genital tract?

A
  • 10% leukemia (AML>ALL); esp M4-M5
  • 10% solid tumour: squamous cell head/neck
  • 3% liver tumour: adenoma and hepatoma
  • 6-8% female genital tract
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15
Q

Fanconi anemia: risk of doing HSCT in context of malignancy?

A
  • Secondary squamous cell carcinoma risk increased by 4X from THEIR already increased risk
  • Age of solid tumours shifted 16 years earlier
  • Solid tumour risk associated with inflammation from GVHD
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16
Q

Fanconi Anemia: Why is early diagnosis of solid tumours especially important?

A

-May allow for surgical approach to solid tumours

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17
Q

What is dyskeratosis congenita?

A

Ectodermal dysplasia, DNA repair defect

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18
Q

Dyskeratosis congenita classic triad?

A
  • Reticulated skin hyperpigmentation
  • Dystrophic nails
  • Mucous membrane leukoplakia (develops with age)
  • Do not need classical triad or physical stigmata for diagnosis*
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19
Q

Dyskeratosis congenita incidence of AA?

A

-Up to 50% in 2nd to 3rd decade

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20
Q

Dyskeratosis congenita: Malignancy risk?

A
  • Solid organ cancers of head, neck, GI: carcinomas of bronchus, tongue, larynx, esophagus, pancreas, AND skin
  • Leukemia in 3rd to 4th decades - MDS/AML
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21
Q

Dyskeratosis congenita: clinical features, especially key ones?

A
  • Pulmonary disease (problematic in transplant)
  • Hair loss, early greying
  • White patch of hair
  • Dental anomalies
  • Esophageal stricture
  • GI disorders
  • Ataxia
  • Epiphora (watery eyes)
  • Hyperhidrosis
  • Hypogonadism
  • Microcephaly
  • Urethral stricture/phimosis
  • Osteoporosis
  • Deafness
  • Cognitive/developmental delay
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22
Q

Inheritance of dyskeratosis congenita?

A

-Autosomal dominant, recessive, and X-linked

23
Q

Hall mark of telomere biology disorder diagnosis?

A

-VERY short telomeres: <1%ile for age in >3 LYMPHOCYTE SUBSETS

24
Q

What is a telomere?

A
  • Protein-DNA complex at end of chromosomes
  • Prevent premature shortening (aging)
  • Prevent end-to-end fusions, translocations, breaks
25
Q

Most common mutations in dyskeratosis congenita and their inheritance patterns?

A
  • DKC1 - 17-36% - X-linked
  • TINF2 - 11-24% - AD
  • hTERC - 6-10% - AD
  • hTERT - 1-7% - AD/AR
26
Q

Treatment of dyskeratosis congenita?

A
  • Supportive care
  • Androgens and cytokines caution about viscous rupture with androgens
  • HSCT with reduced intensity; pulmonary toxicity and issue (often delayed); increased risk of veno-occlusive disease
27
Q

What are telomeres comprised of?

A

Tandem TTAGGG repeats associated with shelterin protein complex

28
Q

What do telomeres do?

A

Facilitate terminal DNA replication and prevent chromosomal rearrangements resulting from free DNA ends

29
Q

Hematologic findings in Shwachman-Diamond Syndrome?

A
  • Fluctuating neutropenia, impaired chemotaxis
  • 1/3 - anemia; 20% - thrombocytopenia
  • Aplasia in 10-25%–> MDS/AML
30
Q

Other clinical findings in Shwachman-Diamond Syndrome?

A
  • Exocrine pancreatic insufficiency, transaminitis
  • Low trypsinogen (<3yo), pancreatic isoamylase (>3yo), fecal elastase
  • Fatty pancreas on imaging
  • Metaphyseal chondroplasia (bell-shaped chest)
  • Short stature
  • Icthyosis/eczema
  • Cardiac
  • Endocrine
  • Developmental
31
Q

Inheritance of Shwachman-Diamond Syndrome?

A

Autosomal recessive

32
Q

Mutations in Shwachman-Diamond Syndrome?

A

-SBDS gene in 90% (7 centromere: 7p12-q11) - or adjacent pseudogene SBDSP

33
Q

What mutations cause “SDS-like” disease, and what is their inheritance?

A
  • SRP54 (AD)
  • DNAJC21 (AR)
  • ELF1 (AR)
34
Q

Function of SBDS?

A
  • Ribosome biogenesis (associates with 60S subunit, promotes 40S:60S ribosome joining)
  • Mitotic spindle stabilization
  • Other, unknown?
35
Q

Shwachman-Diamond: Differential diagnosis

?

A
  • Cystic fibrosis
  • Severe congenital neutropenia: Kostmann Syndrome, Cyclic Neutropenia
  • Pearson syndrome
36
Q

Schwachman-Diamond: Management?

A
  • Pancreatic enzyme replacement (ADEK supplements)
  • Management of congenital anomalies
  • G-CSF - least amount for the shortest time o avoid severe infections if they are a problem
  • Transfusions (irradiated)
  • Monitoring for MDS/AML - periodic/annuual marrow
  • HSCT - variable results due to toxicity
37
Q

Common chromosomal changaes found in SDS?

A

Del 20q, iso 7 q - very common. May not indicate progression to MDS. Monitor more closely.

38
Q

What is Severe Congenital Neutropenia? Other name?

A
  • Heterogeneous disorder of myelopoiesis; mechanism is accelerate apoptosis of myeloid precursors, and maturational arrest at myelocyte/promyelocyte stage
  • ANC<0.5, most <0.2 from birth
  • Early, severe bacterial infections (S.aureus, Pseudomonas)
  • Kostmann syndrome
39
Q

Other hematologic findings in severe congenital neutropenia?

A

-Monocytosis, eosinophilia

40
Q

Natural history of severe congenital neutropenia?

A

-Classically infection, tooth/jaw bone loss, death by age 20

41
Q

Dosing of G-CSF in severe congenital neutropenia, and target?

A
  • 3-100mcg/kg/day

- Goal ANC ~1

42
Q

What is the risk of MDS/AML in severe congenital neutropenia? What cytogenetic abrnormalities?

A
  • 2%/year (higher on G-CSF)

- -7, +21 common

43
Q

Common gene in SCN and cyclic neutropenia? What makes them different?

A
  • ELA-2 “Elane”

- Different exons

44
Q

Genetic mutation in cyclic neutropenia?

Inheritance?

A
  • Heterozygous mutations in Elane SCN2. Mutations near active site (vs. other face in SCN)
  • Autosomal dominant inheritance and sporadic
45
Q

What is cyclic neutropenia?

A
  • ANC <0.2 x 3-5 days in cycles of 21+/-7 days
  • Marrow arrest at myelocyte level
  • Fever, pharyngitis, aphthous ulcers, periodontitis
  • Can have cyclic platelets and reticulocytes also
  • Symptoms often improve with age
46
Q

Management of cyclic neutropenia?

A
  • Aggressive care for infections

- GCSF - can be alternate days, but usually through the month

47
Q

What is myelokathexis/WHIM syndrome?

A
  • Neutropenia with Warts, Hypogammaglobulinemia, Infections, Myelokathexis
  • Noncyclic neutropenia with myeloid HYPERplasia of the marrow - Kathexis/retention of myeloid cells in marrow
48
Q

What are patients with myelokathexis/WHIM syndrome particularly susceptible to?

A

Human papillomavirus

49
Q

Hematopathologic finding in myelokathexis/WHIM syndrome?

A

-Retained cells with condensed nuclei connected by stringy filaments and vacuolated cytoplasm

50
Q

Myelokathexis/WHIM syndrome genetics? Inheritance?

A
  • CXCR4 on 2q22.1 –> gain of function defect, limits down regulation after stimulation
  • Autosomal dominant
51
Q

Role of G-CSF in myelokathexis/WHIM syndrome?

A

-Ameliorates neutropenia, apoptosis and hypogammaglobulinemia

52
Q

Diamond-Blackfan Anemia: diagnostic criteria?

A

-Age <1 y o
-Macrocytic anemia
-Reticulocytopenia
-Paucity of erythroid precursors in the marrow
Supporting:
-Major criteria
–Pathogenic mutations
–Positive family history
-Minor criteria
–Elevated red cell ADA
–Congenital anomalies
–Elevated Hb F
–No other bone marrow failure syndrome
-Classic DBA: All diagnostic criteria
-Non-classic DBA: various combinations
Can have neutropenia, rarely thrombocytopenia

53
Q

Diamond Blackfan anemia: Congenital anomalies?

A
  • In 47% of patients. >20% with more than one anomaly
  • Cranio-orofacial (tow-coloured hair, blue sclerae, glaucoma) - 50%
  • Upper extremity (thumbs, may be subtle) - 38%
  • Genitourinary - 39%
  • Cardiac - 30%
  • Short stature and bony abnormalities are common and often overlooked
54
Q

Diamonnd Blackfan Anemia: Genetics? Inhereitance?

A
  • Mutations/deletions in ribosomal proteins:
  • -RPS19 (DBA1) 19q13.2 - 25% of patients
  • -RPL5, RPS10, RPL11, RPL35A, RPS26, RPS24, RPS17, RPS7, RPL19, RPL26
  • 25-40% of patients with unknown mutations
  • Autosomal dominant or sporadic
  • Special case: acquired haploinsufficiency in RPS14 in the 5q- MDS commonly seen in adults

ASPHO Lectures 2021 (10 decks)

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