Bone Marrow Failure ✅ Flashcards
What happens in bone marrow failure?
There is reduced blood cell production due to defects in the number and function of bone marrow HSCs
What lines of blood cells are affected by bone marrow failure?
Usually affects all the main lines (red cells, white cells, and platelets)
What results from bone marrow failure?
Pancytopenia
Can bone marrow failure affect a single lineage?
Can in some rare conditions
Give 3 examples of conditions causing bone marrow failure affecting a single lineage?
- Red cell aplasia
- Severe congenital neutropenia
- Thrombocytopenia
What are the clinical symptoms of bone marrow failure related to?
The reduction in mature blood cells of each lineage
What are the symptoms of bone marrow failure? -
- Fatigue
- Increased infections
- Bruising and/or bleeding
What are the differential diagnoses for pancytopenia?
- Bone marrow failure syndromes
- Acquired aplastic anaemia
- Acute leukaemia
- Bone marrow infiltration by lymphoma or solid tumours
- Gaucher’s disease
- Osteopetrosis
- Infections, e.g. HIV
- Drugs, including chemotherapy agents
What might suggest a genetic bone marrow failure syndrome?
Blood count abnormalities in combination with physical abnormalities
Give 2 inherited bone marrow failure syndromes that cause pancytopenia?
- Fanconi anaemia
- Shwachman-Diamond syndrome
What physical abnormalities are seen in Fanconi anaemia?
- Short stature
- Microcephaly
- Skin hyperpigmentation
- Upper limb abnormalities
- Renal anomalies
- Genital anomalies
What genes are affected in Fanconi anaemia?
- FANC
- BRCA2
What are the initial investigations done in suspected Fanconi anaemia?
Bone marrow examination
What is the purpose of bone marrow examination in suspected Fanconi anaemia?
- Confirm a hypocellular bone marrow
- Rule out other conditions, including leukaemia
What is the gold standard diagnostic test for Fanconi anaemia?
Chromosomal breakage test
How is the chromosomal breakage test to confirm Fanconi anaemia?
Lymphocytes are cultured to the metaphase state of the cell cycle, in the presence of diepoxybutane (DEB)
What happens in the chromosomal breakage test in Fanconi anaemia?
Spontaneous chromosomal breakages, or chromosomal breakages induced by DEB or mitomycin C
Who else should be tested when a diagnosis of Fanconi anaemia is confirmed?
All siblings
Why should all siblings be tested when there is a confirmed diagnosis of Fanconi anaemia?
Some patients with Fanconi anaemia have very few physical anomalies
What is the pathophysiology of Fanconi anaemia?
It is a disorder of a key DNA repair pathway, which is vital to maintain chromosomal integrity
How many gene mutations have been identified to be involved in Fanconi anaemia?
16
What kind of genes are mutated in Fanconi anaemia?
DNA repair genes
What is the role of the 16 DNA repair genes that can be mutated in Fanconi anaemia?
They participate in a complex network important in DNA repair that orchestrates incisions at sites of cross-linked DNA
What is the role of the 16 DNA repair genes that can be mutated in Fanconi anaemia?
They participate in a complex network important in DNA repair that orchestrates incisions at sites of cross-linked DNA
What is the result of the variety of genetic defects leading to Fanconi anaemia?
Responsible for the pleiotropic features of the Falconi anaemia
What other conditions can Fanconi anaemia increase the risk of?
Leukaemia and other cancers
Who should children with inherited bone marrow failure be managed by?
A specialist MDT
What may be involved in the management of children with bone marrow failure syndromes?
- Observation
- Blood transfusions
- Androgens
- HSCT
When may it be appropriate to have a period of observation in children with bone marrow failure syndromes?
If the patient is relatively well
Give an example of an androgen used in the treatment of bone marrow failure syndromes?
Oxymethalone
What % of patients with bone marrow failure syndromes do androgens produce a therapeutic response in?
50%
What is the limitation of the use of androgens in bone marrow failure syndromes?
- Associated with significant side effects
- Usually only provide transient benefit
What is the limitation of the use of androgens in bone marrow failure syndromes?
- Associated with significant side effects
- Usually only provide transient benefit GiveG
What is the limitation of the use of androgens in bone marrow failure syndromes?
- Associated with significant side effects
- Usually only provide transient benefit
Give a significant side effect that can be seen with androgen therapy?
Hepatocellular carcinoma
What is the role of HSCT in Fanconi anaemia?
It is the only curative treatment for the haematological abnormalities seen
What is the limitation of HSCT in Fanconi anaemia?
It will not reduce the risk of solid tumour malignancies, and children require lifelong monitoring
What physical abnormalities are seen in Shwachmann-Diamond syndrome?
- Pancreatic insufficiency
- Skeletal abnormalities
- Hepatomegaly
What gene is affected in Shwachman-Diamind syndrome?
SBDS
What is the role of the SBDS gene?
It is important for normal ribosome biogenesis
What type of haematological abnormality is particularly seen in Shwachman-Diamond syndrome?
Neutropenia
Give an example of an inherited bone marrow failure syndrome that is associated with anaemia?
Diamond-Blackfan anaemia
What are physical abnormalities seen in Diamond-Blackfan anaemia?
- Short stature
- Thumb abnormalities
- Craniofacial abnormalities
What gene is affected In Diamond-Blackfan anaemia?
RPS19 and other ribosomal genes
Give an example of an inherited bone marrow failure syndrome causing thrombocytopenia?
Thrombocytopenia absent radii (TAR)
What are the physical abnormalities associated with TAR?
- Absent radii
- Facial dysmorphism
- Lower limb anomalies
- Cow’s milk intolerance
What gene is affected in TAR?
RBM8A
What is the inheritance pattern of TAR?
Autosomal recessive
What is TAR characterised by?
- Radial aplasia
- Absent or decreased megakaryocytic in the bone marrow
How does TAR typically present?
Thrombocytopenia
What can TAR cause in the neonatal period?
Significant haemorrhage complications
What is the genetic basis of TAR?
Inheritance of a partial deletion of chromosome 1 in combination with an abnormal copy of the RBM8A gene
What is the aetiology of most cases of acquired aplastic anaemia?
Idiopathic
What are the specific causes of acquired aplastic anaemia?
- Drugs
- Chemicals
- Ionising radiation
- Viruses
Give 2 drugs that can cause acquired aplastic anaemia?
- Chloramphenicol
- Sulphonamides
Give 2 chemicals that can cause acquired aplastic anaemia?
- Benzene
- Pesticides
Give 2 viruses that can cause acquired aplastic anaemia?
- Epstein-Barr virus
- Viral hepatitis
What does the diagnosis of acquired aplastic anaemia require?
Bone marrow biopsy
What is a bone marrow biopsy required for in the diagnosis of acquired aplastic anaemia?
- Confirm marrow hypoplasia
- Rule out other potential causes, particularly leukaemia
What should the history and examination focus on in suspected acquired aplastic anaemia?
Exclusion of any inherited bone marrow failure disorders
What is the mainstay of treatment in acquired aplastic anaemia?
HSCT
How effective is HSCT in acquired aplastic anaemia?
Has an excellent outcome
How are children with acquired aplastic anaemia without a suitable bone marrow donor treated?
Immunosuppresive therapy
Why are children with acquired aplastic anaemia without a suitable bone marrow donor treated with immunosuppressive therapy?
There is evidence that aplasia occurs due to immune dysregulation
Give an immunosuppressive therapy that may be used in the treatment of acquired aplastic anaemia
Anti-thymocyte globulin (ATG)
What is ATG?
An infusion containing antibodies targeted against human T lymphocytes
How effective is ATG in the treatment of acquired aplastic anaemia?
It has been shown to give a good response
What can improve the response to ATG in acquired aplastic anaemia?
Combining it with long-term ciclosporin
