Haem: Myelodysplastic syndromes and Aplastic anaemia Pt.2 Flashcards
List some inherited causes of aplastic anaemia.
RARE
- Fanconi anaemia
- Schwachman-Diamond syndrome
- Dyskeratosis Congenita
Outline the possible pathophysiology of idiopathic aplastic anaemia.
Characterised by failure of the bone marrow to produce blood cells
- Either due to an inherent issue with the stem cells or due to autoimmune attack on stem cells - spontaneous of molecular mimicry perhaps triggered by viral infection
What are the symptoms of aplastic anaemia?
- Anaemic symptoms - fatigue, SoB
- Leukopaenic symtpoms - infections
- Thrombocytopenic symptoms - easy bruising, bleeding
How is aplastic anaemia diagnosed and what would you see?
- FBC - cytopaenia
- Bone marrow biopsy - hypocellularity
How can aplastic anaemia be classified?
Severe (SAA) or non-severe (NSAA)
List some differential diagnosis for pancytopaenia and hypocellular marrow.
- Hypoplastic MDS/AML
- Hypocellular ALL
- Hairy cell leukaemia
- Atypical mycobacterial infection
- Anorexia nervosa (fatty replacement of bone marrow)
- ITP (although Hb and RBC will be normal)
What is the Camitta criteria for severe aplastic anaemia?
1) 2 out of 3 peripheral blood features:
- Reticulocytes < 1% (<20 x 10^9/L)
- Neutrophils < 0.5 x 109/L
- Platelets < 20 x 109/L
2) Bone marrow cellularity < 25%
Outline the management approaches used for bone marrow failure.
- Seek and remove cause
- Supportive (blood products, antibiotics, iron chelation)
- Immunosuppressive therapy (anti-thymocyte globulin, steroids, ciclosporin A)
- Drugs that promote bone marrow recovery (oxymetholone, eltrombopag)
- Stem cell transplantation
- Other treatments for refractory cases - alemtuzumab (T cell depletion), high-dose cyclophosphamide
Such a rare disease, sent to specialist centre with individualised therpy
How might the age of the patient influence decisions regarding their management?
- Immunosuppressive and androgens therapies tend to be used in older patients
- Stem Cell Transplant tends to be used in younger patients (80% cure rate)
List some late complications that occur after immunosuppressive therapy for aplastic anaemia.
- Relapse (35% in 15 years)
- Clonal haematological disorders - 20% risk in 10 years (myelodysplasia, leukaemia, paroxysmal nocturnal haemoglobinuria)
- Solid tumours (3% risk)
What is the most common cause of inherited aplastic anaemia?
Fanconi anaemia
What is the inheritance pattern of Fanconi anaemia?
Autosomal Recessive or X-linked Recessive
What do the gene mutations implicated in Fanconi anaemia tend to result in?
- Abnormalities in DNA repair
- Chromosomal fragility (breakage in the presence of in vitro mitomycin and diepoxybutane)
List some somatic abnormalities that are seen in Fanconi anaemia.
- Short stature
- Hypopigmented spots/café-au-lait spots
- Abnormality of thumbs
- Microcephaly or hydrocephaly
- Hypogonadism
- Developmental delay
(somatic abnormalities - those which you can see)
NOTE: these are only present in 70% of patients
List some complications of Fanconi anaemia.
- Aplastic anaemia (90%) - median age 9
- Myelodysplasia
- Leukaemia
- Cancer (epithelial)
- Liver disease
What are the 3 characteristic features of dyskeratosis congenita?
- Bone marrow failure
- Cancer predisposition
- Somatic abnormalities (80%)
What are the triad of somatic features in dyskeratosis congenita?
- Abnormal skin pigmentation
- Nail dystrophy
- Leukoplakia
What are telomeres and what are their main functions?
Telomeres are repetitive DNA sequences found at the end of chromosomes
- Prevent chromosomal fusion or rearrangements during chromosomal replication
- Protect genes at the end of chromosomes from degradation
Maintenance of telomere length is required for the indefinite proliferation of human cells.
Telomere length is reduced in bone marrow failure diseases (and they are especially short in dyskeratosis congenita)
Which genes are involved in dyskeratosis congenita and what are the inheritance patterns?
- X-linked recessive (MOST COMMON) - DKC1 gene (defective telomere functioning)
- Autosomal dominant - TERC gene (encodes RNA components of telomerase)
- Autosomal recessive - no mutation identified
NOTE: abnormal telomeric structure and function is heavily implicated in dyskeratosis congenita
How is dyskeratosis congenita akin to idiopathic aplastic anaemia?
Short telomeres are seen in both
