UK DBA Registry the first ten years

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UK DBA Registrythe first ten years

• Dr Sarah Ball
• DBA Study Group
• St Georges, London

April 2006
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Aims of registry

• natural history of DBA ?
• prevalence
• life expectancy
• risk of transmission to next generation
• response to treatment
• pathogenesis of DBA ?
• identification of genetic defect(s)?

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basic data of cohort

• born in UK 1975 - 1994
• total 77
• 45 female, 32 male
• prevalence 5 per million
• annual birth rate 770,000
• 7 with positive family history

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Age at presentation
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Diamond Blackfan Anaemia summary of treatment
status at time of study
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initial treatment with steroids
Different outcomes following steroid treatment
transfusion dependent
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prediction of response to steroids

• initial response to steroids 49/68 (72)
• Potential predictive factors
• Gender ? - no
• Age at diagnosis ? - no
• Other physical features of DBA ? - no
• Growth retardation ? - no
• Delay in starting steroid ? - no

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Diamond Blackfan Anaemia patterns of associated
physical abnormalities (dysmorphism)

• I. Unequivocal n22 (35)
• craniofacial abnomalities 20
• plus 1 with mild hypertelorism
• thumb abnormalities in 12
• 1with hypoplastic thumbs as only abnormality
• renal abnormalities in 3
• cardiac abnormalities in 5

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Diamond Blackfan Anaemiapatterns of dysmorphism

• II. equivocal (soft) n 14 (22)
• craniofacial abnormalities mostly affecting eyes
• especially girls
• e.g astigmatism, strabismus, mild epicanthal
  folds
• 1 boy with ? high arched palate, ? normal
• tooth overcrowding
• hypoplastic toenail
• mild pes cavus
• 3 with growth retardation

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Diamond Blackfan Anaemiapatterns of dysmorphism

• III. No dysmorphism
• n 27 (43)
• 7 with growth retardation

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Diamond Blackfan Anaemiasummary of dysmorphism
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UK DBA Registry

• 20 year birth cohort 10 years on

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Original 1975-1994 cohort

• 80 original probands now swelled to 91
• 9 missed first time around
• 2 presented since
• 1 picked up on family studies anaemic age 13
• 1 presented de novo age 11
• Not including mild, subclinical, isolated
  high eADA

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• Plus individuals born since
• 36 born 1995-2000
• Effectively all classical DBA born 1975-2000 in
  UK

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Significant events in original cohort

• 3 bone marrow transplants
• 1 successful
• 1 death
• 1 persistent red cell aplasia

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Significant events in original cohort

• 5 deaths
• cardiac (?viral myocarditis) age 11
• probable cardiac age 18
• endocarditis age 13
• transplant related age 14
• aplastic anaemia age 12

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Significant events in original cohort

• 2 malignancies
• Osteogenic sarcoma

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• But the original registry data collection was a
  snapshot
• Incomplete data on follow up
• Accurate risk of complications not yet known

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What about?

• Growth and puberty
• Haemopoietic progression
• Loss of steroid response
• Risk of clinically significant pancytopenia
• Pregnancy and offspring

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UK DBA Registry

• Family Studies

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overt family history of DBA?
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yes
no
85
n60
n60
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Inheritance patterns in overt familial DBA
2 affected sibs parents normal
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autosomal dominant
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n9
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Family study

• History of anaemia?
• Hb, MCV
• eADA activity

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Prevalence of familial high eADA

• 50 families studied
• Proband and first degree relatives
• No family history of DBA
• 35 families
• both parents and all (if any sibs) had normal
  Hb, MCV and eADA
• 15 families
• first degree relative with high eADA

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35 with normal family results

• 2nd sib in one family also affected despite
  normal results in parents

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Prevalence of abnormal family studies in probands
with no overt FH
family study
normal
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no
family study
abnormal
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n51
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covert familial DBA
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familial DBA
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true sporadic
58
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Inheritance patterns in covert familial DBA
2 or more affected sibs parents normal
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autosomal dominant
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n16
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implications

• genetic counselling
• inheritance pattern in linkage studies
• selection of BMT donor

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DBA Genes

• RPS19 (gene encoding ribosomal protein S19)
  mutated in 20-25 of individuals with DBA
• Useful to confirm family studies, prenatal
  diagnosis, lack of DBA in donor
• Other genes probably also involved with ribosomal
  structure or function

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RPS19
8p
eADA
doesnt quite fit together perfectly just yet
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Future directions for UK DBA Registry

• Revisit original cohort
• Growth, puberty, children
• Treatment
• Still steroid responsive?
• Spontaneous remission?
• Transplant?
• Complications
• of DBA?
• of treatment for DBA?

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• Link with other national registries
• Will increase the chance of finding out about
  rare events in a rare disorder
• Continue the search for the other DBA genes

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With grateful thanks to

• All DBA patients and their families
• DBA UK, and its predecessor One in a Million
• Max Reinhardt Charitable Trust
• All members, past and present, of DBA Study
  Group, St Georges