Congenital Amegakaryocytic Thrombocytopenia
David Czuchlewski, MD
Key Facts
Terminology
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Autosomal recessive disease characterized by
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Thrombocytopenia, usually presenting at birth
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Absence of syndromic malformations or dysmorphism
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Frequent evolution to multilineage bone marrow failure and pancytopenia
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Etiology/Pathogenesis
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Molecular analysis identifies MPL mutations in most CAMT patients
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CAMT inherited loss of function MPL mutations must be differentiated from acquired activating MPL mutations associated with myeloproliferative neoplasms
Microscopic Pathology
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Platelets are morphologically unremarkable
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Megakaryocytes are absent or markedly reduced in number
Top Differential Diagnoses
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Acquired thrombocytopenias are vastly more common than CAMT
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Normal platelet size and absent megakaryocytes help to exclude inherited macro- and microthrombocytopenias
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Fanconi anemia and dyskeratosis congenita can overlap with clinical presentation of CAMT and should be ruled out
Patients with congenital amegakaryocytic thrombocytopenia present at birth or soon after with platelet counts of around 20,000/µL. Platelets that are present  are morphologically normal. |
Congenital amegakaryocytic thrombocytopenia is characterized by absent or markedly reduced megakaryocytes. Other lineages are unaffected, and early in the disease course, cellularity is normal. |
TERMINOLOGY
Abbreviations
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Congenital amegakaryocytic thrombocytopenia (CAMT)
Definitions
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Autosomal recessive disease characterized by
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Thrombocytopenia, usually presenting at birth
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Absence of syndromic malformations or dysmorphism
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Frequent evolution to multilineage bone marrow failure and pancytopenia
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ETIOLOGY/PATHOGENESIS
Overview of Thrombopoietin (TPO) Signaling
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TPO is produced at fairly constant rate
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TPO is removed from circulation by binding to TPO receptors on platelets and megakaryocytes
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TPO receptor is known as MPL (c-Mpl, CD110) and is encoded by gene MPL
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As platelet count increases, more TPO is consumed by platelets bearing MPL and thus less is available to stimulate bone marrow production
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Intact THPO and MPL expression is necessary for both megakaryopoiesis and proper maintenance of other bone marrow progenitor cells
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In knockout mouse models, absence of functional MPL results in reduction of both platelets and stem cells to ˜ 10% of normal
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MPL activation occurs via TPO binding and receptor dimerization
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Further intracellular signaling relies upon JAK-STAT mechanism
MPL Mutations and CAMT
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CAMT is caused by homozygous or compound heterozygous loss of function mutations in MPL
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Clinical features are to some extent determined by location of mutation and consequent degree of alteration to the protein
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Type I mutations are severe mutations that essentially abrogate MPL functionality
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Often these are nonsense mutations
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Type II mutations preserve some MPL function
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These are often missense or splice site mutations
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CAMT-associated MPL mutations must be differentiated from unrelated MPL variants associated with several clinical presentations
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Activating MPL somatic mutations
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In contrast to inherited loss of function mutations in CAMT, these acquired activating mutations increase MPL signaling and result in thrombocytosis
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Acquired activating MPL mutations are seen in some myeloproliferative neoplasms
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MPL polymorphisms not associated with CAMT
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Single nucleotide polymorphism (SNP) G1238T (clinically termed MPL Baltimore) is associated with reduced MPL expression but paradoxical thrombocytosis
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G1238T is most prevalent in African-Americans
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