mistaken diagnosis of hereditary ITP

1
mistaken diagnosis of hereditary ITP

• Charles Eby
• June 18, 2004

2
case presentation

• 25 year old woman referred to a heme/onc
  physician for evaluation of asymptomatic
  thrombocytopenia
• Her sister, mother, and maternal uncle also had
  low platelet counts, but were not symptomatic
• CBC report WBC 5.5 Hgb 12.9 Plt 13,000 low
  platelet count confirmed by manual method

3

• Bone marrow biopsy/aspirate performed
• Pathologist findings
• peripheral blood only truly notable finding was
  the presence of marked thrombocytopenia with plt
  count 26,000. Some of the scattered platelets
  are rather large forms
• Biopsy/aspirate 55 cellularity, ME 31, normal
  maturation, megakaryocytes show no consistent
  changes in cytoplasmic granularity or nuclear
  ploidy
• Final diagnosis marked thrombocytopenia with
  mild megakaryocytic hyperplasia

4

• Patient given diagnosis of familial ITP
• Prednisone 60 mg/d x 2 weeks
• Plt counts
• Day 1 19,000
• Day 4 28,000
• Day 9 41,000
• Day 14 28,000
• Assessment non-responder to prednisone,
  recommended splenectomy
• Patient requested 2nd opinion

unable to accurately assess plt count due to
significant numbers of giant and/or large
platelets, as a result, plt count may be falsely
decreased
5

• Physical exam unremarkable
• ROS easy bruising
• PMH 4 teeth extracted w/o excess bleeding
• FH

?
?
S 1976
Nl plt count Giant plt spouse
S 1970
6
peripheral smear review
Auto plt count 15,000 Manual plt count 60,000
7
hereditary macrothrombocytopenia

• Autosomal recessive inheritance
• Bernard-Soulier syndrome GPIb-X-V defects
• Autosomal dominant inheritance
• Gray platelet syndrome a granule deficiency
• Mediterranean macrothrombocytopenia
• Thrombocytopenia, giant platelets, and leukocyte
  inclusions
• May-Hegglin Anomaly

8
May Hegglin Anomaly (MHA)clinical/laboratory
features

• Clinical
• RARE
• Mild bleeding history
• Immunocompetent
• May be accompanied by
• Premature hearing loss
• Premature cataracts
• Glomerulonephritis and ESRD

• Laboratory
• Platelet size and number vary widely
• Leukocyte inclusions vary in prevalence and size
• Bleeding time, plt aggregation studies typically
  normal

9
MHA subtypes
First reported 1909, 1945
1990 1985 1972
Medicine 2003203-215, 2003
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ultrastructure of döhle bodies
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ultrastructure of döhle-like bodies
James White et al. Blood 65397-406, 1985
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systematic evaluations blur MHA subtype boundries
Medicine 82203-215, 2003
13
molecular basis of MHA

• 1999-2000 linkage analysis localized MHA, SBS,
  and FTNS to chromosome 22q12-13
• MYH9 of particular interest non muscle myosin
  heavy chain type IIA
• 2000 two groups independently identified
  mutations in MYH9 that co-segregated with the
  phenotypes
• May-Hegglin/Fechtner syndrome consortium, and
  Kelly et al.
• Nature Genetics 2000, 26103-108.

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döhle-like bodies contain non-muscle myosin
IIABr J Haem 117164-67, 2002
control
hereditary macrothrombocytopenia patients
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actin-myosin structure-function
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MYH9 mutations
Am J Hum Genet 691033-45, 2001
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Summary of mutations
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MYH9 mutations and cell biology

• Megakaryopoiesis platelet budding
• Platelet activation and shape change
• Platelet glycoprotein expression
• Neutrophil chemotaxis
• Podocyte contraction
• Cochlear stereocilia
• lens

21
clinical follow-up
S 1976
S 1970
22
summary

• MYH9 mutations define a single allelic disorder,
  (macrothrombocytopenia, and leukocyte inclusions)
  with variable expression of renal, cochlear, and
  optic lens defects