Haem: Myelodysplastic syndromes and Aplastic anaemia Pt.2

Question 1

List some inherited causes of aplastic anaemia.

Answer 1

RARE

• Fanconi anaemia
• Schwachman-Diamond syndrome
• Dyskeratosis Congenita

Question 2

Outline the possible pathophysiology of idiopathic aplastic anaemia.

Answer 2

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

Question 3

What are the symptoms of aplastic anaemia?

Answer 3

• Anaemic symptoms - fatigue, SoB
• Leukopaenic symtpoms - infections
• Thrombocytopenic symptoms - easy bruising, bleeding

Question 4

How is aplastic anaemia diagnosed and what would you see?

Answer 4

• FBC - cytopaenia
• Bone marrow biopsy - hypocellularity

Question 5

How can aplastic anaemia be classified?

Answer 5

Severe (SAA) or non-severe (NSAA)

Question 6

List some differential diagnosis for pancytopaenia and hypocellular marrow.

Answer 6

• 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)

Question 7

What is the Camitta criteria for severe aplastic anaemia?

Answer 7

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%

Question 8

Outline the management approaches used for bone marrow failure.

Answer 8

1. Seek and remove cause
2. Supportive (blood products, antibiotics, iron chelation)
3. Immunosuppressive therapy (anti-thymocyte globulin, steroids, ciclosporin A)
4. Drugs that promote bone marrow recovery (oxymetholone, eltrombopag)
5. Stem cell transplantation
6. Other treatments for refractory cases - alemtuzumab (T cell depletion), high-dose cyclophosphamide

Such a rare disease, sent to specialist centre with individualised therpy

Question 9

How might the age of the patient influence decisions regarding their management?

Answer 9

• Immunosuppressive and androgens therapies tend to be used in older patients
• Stem Cell Transplant tends to be used in younger patients (80% cure rate)

Question 10

List some late complications that occur after immunosuppressive therapy for aplastic anaemia.

Answer 10

• Relapse (35% in 15 years)
• Clonal haematological disorders - 20% risk in 10 years (myelodysplasia, leukaemia, paroxysmal nocturnal haemoglobinuria)
• Solid tumours (3% risk)

Question 11

What is the most common cause of inherited aplastic anaemia?

Answer 11

Fanconi anaemia

Question 12

What is the inheritance pattern of Fanconi anaemia?

Answer 12

Autosomal Recessive or X-linked Recessive

Question 13

What do the gene mutations implicated in Fanconi anaemia tend to result in?

Answer 13

• Abnormalities in DNA repair
• Chromosomal fragility (breakage in the presence of in vitro mitomycin and diepoxybutane)

Question 14

List some somatic abnormalities that are seen in Fanconi anaemia.

Answer 14

• 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

Question 15

List some complications of Fanconi anaemia.

Answer 15

• Aplastic anaemia (90%) - median age 9
• Myelodysplasia
• Leukaemia
• Cancer (epithelial)
• Liver disease

Question 16

What are the 3 characteristic features of dyskeratosis congenita?

Answer 16

• Bone marrow failure
• Cancer predisposition
• Somatic abnormalities (80%)

Question 17

What are the triad of somatic features in dyskeratosis congenita?

Answer 17

• Abnormal skin pigmentation
• Nail dystrophy
• Leukoplakia

Question 18

What are telomeres and what are their main functions?

Answer 18

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)

Question 19

Which genes are involved in dyskeratosis congenita and what are the inheritance patterns?

Answer 19

• 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

Question 20

How is dyskeratosis congenita akin to idiopathic aplastic anaemia?

Answer 20

Short telomeres are seen in both