Alice Norton Georgina Hall Paresh Vyas Department of Haematology and MRC Molecular Haematology Unit John Radcliffe Hospital and Weatherall Institute of Molecular Medicine Oxford Background Neonates and children with Down syndrome DS are predisposed to blood disorders ID: 933981
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Slide1
A Study of Haematology in newborns with Down syndrome
Alice Norton, Georgina Hall, Paresh Vyas
Department of Haematology and MRC Molecular Haematology Unit
John Radcliffe Hospital and Weatherall Institute of Molecular Medicine, Oxford
Slide2Background
Neonates and children with Down syndrome (DS) are predisposed to blood disorders
Birth
Low platelets -- predisposed to bleeding Polycythaemia -- increased blood viscosity Neonatal preleukaemic disorder -TAM Incidence unknownChildhood ~ 1-3 % of DS children get Acute Leukaemia
Slide3Transient Abnormal Myelopoiesis (TAM)
TAM also known as TMD or TL
Presents at birth. Incidence unknown but suggested to be ~10-20%
Variable presentationUsually asymptomatic with mild disturbance in blood countIt can be missedTAM is a form of preleukaemia -- in ~30% it marks later development of Acute Myeloid Leukaemia
Slide4Myeloid Leukaemia of Down Syndrome (ML-DS)
~1% of DS children develop ML-DS. X500 fold increased risk
Median age of presentation is 1.8 yrs. Most cases children are <5 years
Management6-8 month intensive chemotherapy - mainly as an in-patient.Leukaemia is chemosensitive. ~85% cure rate. Most of the deaths are due to treatment toxicity not leukaemia resistance New European protocol. .ML-DS and TAM are a unique pair of linked conditions.
Slide5TAM and ML-DS in Down Syndrome
TAM
ML-DS
SpontaneousremissionDS neonate
NORMAL
10-20%
80-90%
30%
70%
Slide6GATA1 mutations in ML-DS and TAM
TAM and ML-DS samples specifically have acquired a mutation in the transcription factor GATA1
MKP
MK
PLATELETS
GATA1 coordinates
-- growth arrest
-- terminal maturation platelet release
Vyas et al Blood 1999, Vyas PNAS 2000
Wechsler et al Nature Gen 2002
Ahmed et al Blood 2004
In cases that had TAM followed by AMKL they are the same mutation is present at both stages of the disease - thus the diseases are molecularly linked.
Ahmed et al BLOOD 2004
All cases of TAM and ML-DS acquire GATA1 mutations in fetal life.
Ahmed et al BLOOD 2004
Slide7GATA1 mutations and TAM and ML-DS
Normal
Remission
NormalNormalDS NeonateDS Fetus
DS Neonate
ML-DS
? TAM
No signs
TAM with
clinical
signs
GATA1
Mutation
No GATA1 Mutation
Small
clone
Large clone
Clonal extinction
Clonal extinction
Clonal expansion
Additional events
Clonal expansion
Additional events
Slide8Can we identify a neonate with DS with a GATA1 mutation?
What is the blood count and film of DS neonate with/without a GATA1 mutation?
What is the incidence of GATA1 mutation in DS neonates?
Can we predict those DS children that will inevitably develop ML-DS?Can we identify when a GATA1 mutation is normally lost?Clinical QuestionsDS neonateGATA1 mutant cloneML-DS
GATA1mutant clone
1-5 years of age
Birth
Normal
GATA1 mutant clone lost
Slide9Prospective study of blood abnormalities in DS neonates
What is the spectrum of haematological abnormalities in Down syndrome neonates with and without GATA1 mutation
Incidence of TAM and ML-DS
Prevalence of GATA1 mutations in neonates/children with DSCan we predict who will get ML-DS
Slide10GATA1 mutations in DS TMD and AMKL
All cases of TAM and ML-DS have an acquired mutation in the key megakaryocyte transcription factor GATA1 that are disease-specific.
Ahmed et al BLOOD 2004 Carpeter et al BJH 2005
Hellebostad et al JPHO 2005 In cases that had TAM followed by AMKL they are the same mutation is present at both stages of the disease - thus the diseases are molecularly linked Ahmed et al BLOOD 2004All cases of AMKL acquire GATA1 mutations in fetal life Ahmed et al BLOOD 2004 Germline GATA mutation in a normal karyotype child/adult never cause leukaemia.
Slide11REC approved prospective DS cohort studies
Can we identify a neonate with DS with a GATA1 mutation?
UK multi-centre prospective population-based longitudinal cohort study. Largest such study of DS newborns.
Oxford Leeds Glasgow DublinRecruit 150 neonates with Down syndrome (~350 born annually). FBC and blood film. Central review of blood films. GATA1 mutation analysis.Alice Norton, Georgina Hall, Irene Roberts, Chris Halsey, Brenda Gibson, Aengus O’Marcaigh, Rebecca James, Sally Kinsey, Eve Roman.
Can we predict those DS children that will inevitably develop ML-DS?
Yearly haematology and GATA1 mutation analysis.
Slide12Cohort study: Participating Hospitals
Patients recruited to study:
North Middlesex Hospital
(2)Whittington Hospital (1)Northwick Park Hospital (4)Chelsea and Westminster (6)Hillingdon Hospital (3)St Thomas’ Hospital, London (1)Whipps Cross Hospital (7)Queen Charlottes Hospital (2)Birmingham Heartlands (5)Rosie Maternity, Cambridge (12)John Radcliffe, Oxford (6) Swindon Hospital (1)RHSC, Edinburgh (1)RHSC, Glasgow (2)Birmingham Women’s (1)New Cross Hospital (1)Still awaiting recruitment:St Mary’s Hospital, LondonHomerton HospitalNorth Staffordshire HospitalRoyal Shrewsbury HospitalMilton Keynes HospitalTotal recruited patients = 55
Slide13Neonatal Study: Preliminary Results
Thrombocytopenia: 63%
IUGR: 15%
Platelet clumping: 30%Polycythaemia: 37%Cardiac dysfunction: 17%IUGR: 15%Neutrophilia: 50%35% of those with neutrophilia, leucocytosis and/or lymphocytosis had clinical features of infection
TMD 9%
Slide14THROMBOCYTOPENIA:
Platelets <150: 63%
Slide15More samples and centers please
Local R&D is required - Dr Norton will help with this.
Local center identifies baby/family.
PIS and consent obtained by local team or Dr Norton will come to do this.FBC and blood film collected within 2 weeks of birth - heel prick is fine.FBC and film is reported on by experienced paediatric haematologists. Report is issued with advice if required.Store DNA for GATA1 mutation analysis at later stage.
Slide16Long term follow-up study (1)
Analysis of stored first (birth) sample for GATA1 mutation
Follow-up initial cohort on yearly basis for 5 years
FBCBlood filmClinical questionnaireGATA1 mutationsREC approvedDr Norton will contact local centresPIS sent to family homeDr Norton will contact family to discuss if family are happyto participateConsent and sample taken at routine clinic visit by local team or Dr Norton
Slide17Long term follow up study (2)
Blood sample (0.5 ml) taken at a time when
other blood samples taken (TFT)
Finger prick is fine Feed back will be of the FBC and film but notGATA1 test result
Slide18Contact details
If you would like to collaborate in the study please contact:
Dr Alice Norton or Dr Paresh Vyas Weatherall Institute of Molecular Medicine John Radcliffe Hospital Oxford OX3 9DU Telephone numbers: Dr Norton 01865 222410 Dr Vyas 01865 222309 Fax number 01865 222501 and 01865 222500 E-mail: Dr Norton nortal40@hotmail.com Dr Vyas paresh.vyas@imm.ox.ac.uk
Slide19Acknowledgements
Alice Norton Georgina Hall
John Radcliffe Hospital, Oxford
Irene RobertsHammersmith Hospital, LondonSally Kinsey/Beki James/Eve RomanLeeds/YorkDMIG