Bone Marrow Failure Flashcards
Examples of Inherited Bone Marrow Failure Syndromes (IBMFS)?
- Fanconi Anemia
- Dyskeratosis Congenita
- Diamond-Blackfan Anemia
- Scwachman-Diamond Syndrome
- Congenital Amegakaryocytic Thrombocytopenia
- Thrombocytopenia Absent Radii
- Severe Congenital Neutropenia
Etiologies of acquired aplastic anemia?
- Medications
- Chemicals
- Toxins
- Viral infection
- PNH
- Idiopathic (immune)
Fanconi Anemia - cancer predispositions?
- MDS/AML
- Squamous cell carcinoma (oral, vaginal vulvar)
- Brain tumours
- Wilms tumours
- Other solid tumours
Fanconi Anemia - most common congenital anomalies? Classic one?
- Skin - cafe au lait or hypopigmentation
- Short stature
- Classic: Upper limb - hypoplastic or absent radii (and absent thumb)
Fanconi anemia - diagnosis? If high clinical suspicion, but equivocal test? Role of mutation analysis? Other less commonly used test?
- 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
Why can chromosomal breakage studies be falsely normal on PB? What to do?
- 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
Inheritance of Fanconi anemia?
-Autosomal recessive EXCEPT for FANC-B (X-linked recessive)
What do the Fanconi genes code for?
Nuclear protein complex that repairs DNA
Most common genetic abnormalities for Fanconi anemia?
- FANC-A; 16q24.3 (60-70%0
- FANC-C; 9q22.3 (10-15%)
Fanconi anemia: Examples of mutation or complementation group predicting clinical course?
- 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
Fanconi anemia: medications to slow count decline?
- Oxymethalone (androgen)
- Danazol - less virilizing for females
Side effects of androgens? Monitoring requirements?
- 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
Risk of malignancy in Fanconi Anemia?
- 1000X greater than normal
- 30% by adulthood
Incidence of leukemia in Fanconi anemia? Solid tumour? Liver tumour? Female genital tract?
- 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
Fanconi anemia: risk of doing HSCT in context of malignancy?
- 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
Fanconi Anemia: Why is early diagnosis of solid tumours especially important?
-May allow for surgical approach to solid tumours
What is dyskeratosis congenita?
Ectodermal dysplasia, DNA repair defect
Dyskeratosis congenita classic triad?
- Reticulated skin hyperpigmentation
- Dystrophic nails
- Mucous membrane leukoplakia (develops with age)
- Do not need classical triad or physical stigmata for diagnosis*
Dyskeratosis congenita incidence of AA?
-Up to 50% in 2nd to 3rd decade
Dyskeratosis congenita: Malignancy risk?
- Solid organ cancers of head, neck, GI: carcinomas of bronchus, tongue, larynx, esophagus, pancreas, AND skin
- Leukemia in 3rd to 4th decades - MDS/AML
Dyskeratosis congenita: clinical features, especially key ones?
- 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
Inheritance of dyskeratosis congenita?
-Autosomal dominant, recessive, and X-linked
Hall mark of telomere biology disorder diagnosis?
-VERY short telomeres: <1%ile for age in >3 LYMPHOCYTE SUBSETS
What is a telomere?
- Protein-DNA complex at end of chromosomes
- Prevent premature shortening (aging)
- Prevent end-to-end fusions, translocations, breaks
Most common mutations in dyskeratosis congenita and their inheritance patterns?
- DKC1 - 17-36% - X-linked
- TINF2 - 11-24% - AD
- hTERC - 6-10% - AD
- hTERT - 1-7% - AD/AR
Treatment of dyskeratosis congenita?
- 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
What are telomeres comprised of?
Tandem TTAGGG repeats associated with shelterin protein complex
What do telomeres do?
Facilitate terminal DNA replication and prevent chromosomal rearrangements resulting from free DNA ends
Hematologic findings in Shwachman-Diamond Syndrome?
- Fluctuating neutropenia, impaired chemotaxis
- 1/3 - anemia; 20% - thrombocytopenia
- Aplasia in 10-25%–> MDS/AML
Other clinical findings in Shwachman-Diamond Syndrome?
- 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
Inheritance of Shwachman-Diamond Syndrome?
Autosomal recessive
Mutations in Shwachman-Diamond Syndrome?
-SBDS gene in 90% (7 centromere: 7p12-q11) - or adjacent pseudogene SBDSP
What mutations cause “SDS-like” disease, and what is their inheritance?
- SRP54 (AD)
- DNAJC21 (AR)
- ELF1 (AR)
Function of SBDS?
- Ribosome biogenesis (associates with 60S subunit, promotes 40S:60S ribosome joining)
- Mitotic spindle stabilization
- Other, unknown?
Shwachman-Diamond: Differential diagnosis
?
- Cystic fibrosis
- Severe congenital neutropenia: Kostmann Syndrome, Cyclic Neutropenia
- Pearson syndrome
Schwachman-Diamond: Management?
- 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
Common chromosomal changaes found in SDS?
Del 20q, iso 7 q - very common. May not indicate progression to MDS. Monitor more closely.
What is Severe Congenital Neutropenia? Other name?
- 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
Other hematologic findings in severe congenital neutropenia?
-Monocytosis, eosinophilia
Natural history of severe congenital neutropenia?
-Classically infection, tooth/jaw bone loss, death by age 20
Dosing of G-CSF in severe congenital neutropenia, and target?
- 3-100mcg/kg/day
- Goal ANC ~1
What is the risk of MDS/AML in severe congenital neutropenia? What cytogenetic abrnormalities?
- 2%/year (higher on G-CSF)
- -7, +21 common
Common gene in SCN and cyclic neutropenia? What makes them different?
- ELA-2 “Elane”
- Different exons
Genetic mutation in cyclic neutropenia?
Inheritance?
- Heterozygous mutations in Elane SCN2. Mutations near active site (vs. other face in SCN)
- Autosomal dominant inheritance and sporadic
What is cyclic neutropenia?
- 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
Management of cyclic neutropenia?
- Aggressive care for infections
- GCSF - can be alternate days, but usually through the month
What is myelokathexis/WHIM syndrome?
- Neutropenia with Warts, Hypogammaglobulinemia, Infections, Myelokathexis
- Noncyclic neutropenia with myeloid HYPERplasia of the marrow - Kathexis/retention of myeloid cells in marrow
What are patients with myelokathexis/WHIM syndrome particularly susceptible to?
Human papillomavirus
Hematopathologic finding in myelokathexis/WHIM syndrome?
-Retained cells with condensed nuclei connected by stringy filaments and vacuolated cytoplasm
Myelokathexis/WHIM syndrome genetics? Inheritance?
- CXCR4 on 2q22.1 –> gain of function defect, limits down regulation after stimulation
- Autosomal dominant
Role of G-CSF in myelokathexis/WHIM syndrome?
-Ameliorates neutropenia, apoptosis and hypogammaglobulinemia
Diamond-Blackfan Anemia: diagnostic criteria?
-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
Diamond Blackfan anemia: Congenital anomalies?
- 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
Diamonnd Blackfan Anemia: Genetics? Inhereitance?
- 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
