Down’s Syndrome
Overview
• Down’s Syndrome
• Leukaemia
• Treatment
Down’s Syndrome
Originally described in 1866
Associated with Trisomy 21 in 1959
Prevalence 1/1000 births
95% due to chromosomal non-disjunction; 5% due to translocations
Risk factors:
increased maternal age
1/1000 maternal age 30 years
9/1000 maternal age 40 years
?infertility treatment
Down’s Syndrome
Clinical Features
physical appearance
intellectual disability
developmental delay
sensory abnormalities
cancer
WBC proliferation in the bone
marrow
Classification:
acute/chronic
type of WBC
AML
20% childhood leukaemia; 40% Down’s Syndrome leukaemia
AMKL
6% childhood AML; 62% Down’s Syndrome AML
500 times higher incidence children with Down’s Syndrome compared to
children without Down’s Syndrome
Leukaemia in Down’s Syndrome
AML in Down’s Syndrome
AMKL in most cases
younger median age of onset
2 in Down’s Syndrome
8 in non-Down’s Syndrome
myelodysplastic syndrome more common prior to leukaemia
Transient Leukaemia
Transient Leukaemia
Also termed: ‘Transient Abnormal Myelopoiesis’ and ‘Transient Myeloproliferative
Disorder’
10% newborn infants with Down’s Syndrome
peripheral blood contains clonal population of megakaryoblasts
cannot be distinguished from AMKL blasts by routine methods
usually clinically silent
usually disappear within 3 months
majority of cases totally resolve
However
can be fatal
20% develop MDS and AMKL by the age of 4 years
Transient Leukaemia
Leukaemic cells in Transient Leukaemia and AMKL can:
show variable megakaryocytic differentiation
show features of multiple haematopoietic lineages
Leukaemic cells in Transient Leukaemia and AMKL in Down’s Syndrome can form
megakaryocytic, erythroid or basophillic lineages
GATA1
all Transient Leukaemia and AMKL cases have GATA1 mutations
most abrogate splicing of exon 2 or produce stop codon prior to alternative
start codon at position 84
lack N-terminal domain
mutations disappear upon remission
disease specific mutations
leukemogenisis model: transcription factor mutation blocks differentiation
GATA1 mutation determines haematopoietic lineage
GATA1 mutations present in Transient Leukaemia at birth
mutations in utero
proportion of Down’s Syndrome fetuses acquire GATA1 mutation
large clone = Transient Leukaemia
small clone = no clinical signs
Aetiology
Picture: Hitzler & Zipursky, 2005
Transient
Leukaemia
with clinical
signs of
disease
?Transient
Leukaemia
with no
clinical signs
of disease
Future Research
AML (AMKL)
increased sensitivity to cytarabine
80% 5 year survival
failure usually due to toxicity (mucositis and infection)
ALL
similar treatment as in AML
60-70% cure rate (75-85% in population without Down’s Syndrome)
no increased sensitivity, but increased toxicity
dose reduction would increase risk of relapse
supportive care
References
Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., O’Marcaigh, A., Wynn, R., Stevens, R., Addison, M.,
King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. (2004). Natural History of GATA1 mutations in Down
syndrome, Blood, 103(7):2480-2489.
Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W., Zipursky, A. (2003). GATA1 mutations in transient leukaemia and
acute megakaryoblastic leukaemia of Down syndrome, Blood, 101(11):4301-4304.
Hitzler, J.K., Zipursky, A. (2005). Origins of leukaemia in children with down syndrome, Cancer, 5:11-20.
Puumala, S.E., Ross, J.A., Olshan, A.F., Robison, L.L., Smith, F.O., Spector, L.G. (2007). Reproductive history,
infertility treatment, and the risk of acute leukaemia in children with down syndrome, Cancer, [Epub ahead of
print].
Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A., Orkin, S.H. (1997). A loneage-selective knockout establishes the
critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development, Embo J., 16:3965-
3973.
Slordahl, S.H. et al. (1993). Leukaemic blasts with markers of four cell lineages in Down's syndrome
(‘megakaryoblastic leukaemia’), Med. Pediatr. Oncol., 21:254-258.
Vyas, P., Crispino, J.D. (2007). Molecular insights into Down syndrome-associated leukemia, Current Opinion in
Pediatrics, 19:9-14.
Webb, D., Roberts, I., Vyas, P. (2007). Haematology of Down syndrome, Arch. Dis. Child. Fetal Neonatal Ed.,
[published online 5 Sep 2007].
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