BMF/AA Flashcards
Shwachman-Diamond Syndrome clinical features
- Exocrine pancreatic insufficiency (diarrhea)
- neutropenia
- BMF
- FTT
- skeletal abnormalities (metaphaseal dysplasia, rib cage abnormalities)
- cognitive/behavioural deficits
- 20% risk of MDS/AML by age 20
Shwachman-Diamond Syndrome Genetics
Auto recessive. SBDS (7q11) in 90%
- isochrome 7q seen in 45% of MDS with SDS but rare otherwise
What is the inheritance pattern of Fanconi
99% autosomal recessive
1% x-linked FANC-B
Which fanconi patients have more of a severe course?
FANC-C and FANC-G
What average age do fanconi patients present with aplastic anemia?
8-10 yrs
List indications for fanconi screening
All with aplastic anemia
Children with mds or aml
Those with birth defects suggestive of FA
Development of cancer at young age
(Squamous cell CA <50yr, vulvar CA <40yrs, uterine CA <30yrs)
Patients with excess cafe sugar lait spots
Patients with growth failure
In TAR describe the upper limb abnormalities
Normal thumbs but absent radii
What screening is required in an FA patient on androgen therapy?
Annual liver ultrasound to watch for liver malignancy and peliosis hepatis (blood lake) and liver enzymes to watch for transaminitis
How effective is androgen therapy for FA patients?
Effective in 50% patients
What triad characterizes dyskeratosis congenita
Dysplastic nails
Leukoplakia of oral mucous membranes
Abnormal pigmentation of upper chest and neck
What is median age for onset of pancytopenia in DC?
10 yrs old
What major concerns exist with HSCT for DC
Increased risk of VOD
Increased risk of interstitial pulmonary disease
Risk of pulmonary fibrosis
What is the remission rate for DBA?
20% by age 25
What is the treatment approach for DBA?
Transfusions as needed until 1yr old, then prednisone 2mg/kg/day and then reduce to the most tolerated dose
If after 3 mths not transfusion independent (hgb>90) then stop
Consider HSCT especially those transfusion dependent
Definition of severe aplastic anemia
BM cellularity <25% At least 2 cytopenias: - ANC < 0.5 (if < 0.2 then VSAA) - platelets < 20 - reticulocytes < 20
Treatment plans for SAA
If MRD available then go to HSCT
If not, IST with:
- horse ATG, Methylpred and CSA
- in kids MUD outcomes similar to IST so can consider that as upfront therapy.
If failed IST then MUD or 2nd course with rabbit ATG
If failed 2nd attempt then haplo
ATG side-effects
Headache myalgia arthralgia chillls and fever chemical phlebitis pruritis leukopenia thrombocytopenia serum sickness anaphylaxis
What are the diagnostic criteria for Severe Aplastic Anemia?
vere Aplastic Anemia:
Bone marrow cellularity <25 percent (or 25 to 50 percent if <30 percent of residual cells are hematopoietic)
At least two of the following:
•Peripheral blood absolute neutrophil count (ANC) <500/microL (<0.5 X 109/L)
•Peripheral blood platelet count <20,000/microL
•Peripheral blood reticulocyte count <20,000/microL
What are the diagnostic criteria for very severe aplastic anemia?
the AA criteria and ANC<200
What inherited bone marrow failure disorders present with isolated RBC cytopenias?
DBA
CDA
Pearson Syndrome
What inherited bone marrow failure disorders present with isolated WBC cytopenias?
Severe congenital neutropenia
Shwachman-Diamond
Reticular Dysgenesis
What inherited bone marrow failure disorders present with isolated platelet cytopenias?
CAMT
TAR
What transplant conditioning regimen is used for Fanconi’s anemia
No Radiation!
BuFluCy
What conditioning regimen is used for DKC?
Fludarabine +/- serotherapy
What is the triad of DKC
- reticulated skin pigmentation
- dystrophic nails
- mucous membrane leukoplakia
What are the proposed causes of aplastic anemia?
idiopathic (70%) Secondary: -drugs -chemicals-DDT -toxins-benzene -radiation -infections -immunologic: CVID -MDS -Thymoma -PNH -malnutrition
What 2 cytokines are felt to play a central role in the pathophys of aplastic anemia?
Interferon gamma
TNF
What is the most common mutation leading to Fanconi anemia?
FANC-A approx 60-70% patients
associated with a later onset of bone marrow failure, around 4yrs old
up to what percentage of fanconi patients lack any physical features?
40%
What cancer surveillance is required in a fanconi patient?
yearly bone marrow to assess for MDS/leukemia
yearly head and neck exam over age 7
yearly gyne exam begininning at age 16
breast self exam beginning at age 16
periodic oral cancer and dermatologic screening
What mutation causes Kostmann syndrome?
homozygous mutation in the HAX1 gene on chromosome 1
Mutation in what gene causes Severe Congenital Neutropenia?
ELANE gene (neutrophil elastase gene)-mutations cause high rate of premature apoptosis in neutrophil precursors causing decreased myelopoiesis these mutations only affect one allele, is usually AD or sporadic inheritance
A patient with SCN what does the CBC show?
Normal WBC, with ANC <200 and compensatory eosinophilia and monocytosis.
Patients can have mild anemia and thrombocytosis
What is the initial treatment for SCN?
use G-CSF 5ug/kg/day
expect response in 7-10 days
adjust dose to achieve ANC 1000-1500
What % of patients with SCN respond to G-cSF?
> 95% will respond
What clonal abnormality is more commonly associated with SCN
monosomy-7
What are the indication for HSCT for patients with SCN?
- Patients who require >8ug.kg/day of G-CSF are more likely to succumb to infection or leukemia
- Refractory to G-CSF
- Developing MDS/AML
Should consider HSCT for all patients with HLA matched sibling
What is reticular dysgenesis?
disorder of stem cells in which maturation of myeloid and lymphoid lineages is defective
Platelets and RBCs are normal
Patients have severe neutropenia and moderate to severe lymphopenia
Theres an absence of peripheral lymphoid tissues-tonsils, peyers patches, splenic follicles
Mortality rate is high from infection at an early age
HSCT can be curative
For FA patients how many respond to androgens?
What surveillance should be done when taking androgens?
50% respond
Should have yearly abdominal U/S to look for liver tumours or peliosis hepatis (blood lakes)
and LFTs to watch for transaminitis
For DKC what is the median age for onset of pancytopenia?
10yrs old
50% develop SAA by age 50yrs old
For DKC patients what and when do they develop cancers?
usually in the 3rd-4th decade
Get AML, carcinomas of the bronchus, tongue, larynx, esophagus, skin and pancreas
For HSCT in DKC what are the main concerns/considerations?
Increased risk of VOD (reason unknown)
High risk of interstitial pulmonary disease during HSCT
Development of pulmonary and hepatic fibrosis
Describe the treatment approach for DBA patients?
Before 1yr transfuse as needed
Prednisone 2mg/kg/day and achieve goal of Hb>90, then reduce to lowest possible
For DBA what is considered treatment failure for steroids?
If Prednisone at 2mg/kg/day for 2-3 months has no effect on making patient transfusion independent, then is a failure
What is the response rate to steroids for patients with DBA?
80% initally will respond, but the actual remission rate is 20% by age 25yr
What are the mechanisms of action for each bone marrow failure syndrome? DBA DKC FA SCN
DBA-ribosome biosynthesis problem
DKC-deficient telomerase activity
FA-DNA repair defect
SCN-mutation in ELANE gene causing premature apoptosis of neutrophil precursors
What is the definition of TEC?
spontaneous cessation of erythropoiesis in an otherwise healthy child
What are the diagnostic criteria for DBA?
Classical criteria:
- normochromic, usually macrocytic anemia
- reticulocytopenia
- normocellular marrow with paucity of erythroid precursors
- age less than 1yrs
Supporting criteria:
Definitive but not essential:
presence of mutation described in classical DBA
Major: positive family history Minor: congenital abnormalities described in classical DBA macrocytosis elevated fetal Hb elevated eADA
What is GATA1?
a transcription factor important for erythrocyte and megakaryocyte development
For TAR what upper limb abnormalities are seen?
both thumbs are present, there is bilateral absence of radii
What is the expected prognosis for TAR patients?
2/3 can recover their platelet counts spontaneously around 12-24mths, however the eventual recovered platelet count isn’t completely normal
What CBC finding are seen in patients with TAR?
very low platelets, usually diagnosed in utero or day 1 of life
WBC elevation is commonly seen
anemia can be seen
For CAMT at what age due patients progress to aplastic anemia?
usually by 5yrs old
aim is to do HSCT by 6-12 months old
