Constitutional Disorders_Hemepath Boards
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What two disorders cause small platelets? Hypogranular platelets?
- 1) X-linked amegakaryocytic thrombocytopenia, Wiscott-Aldrich syndrome
- 2) MDS, gray platelet syndrome/alpha granule deficiency (large and hypogranular)
What syndrome causes 1) nonlobated or hypolobated megakaryocytes, 2) giant alpha granules, 3) 11q23.3 deletion, and 4) FLI1 mutation?
All of the following cause decreased/absent megakaryocytes except:
A) Fanconi anemia
B) Dyskeratosis congenita
C) Shwachman-Diamond syndrome
D) Mediterranean macrothrombocytopenia
E) Thrombocytopenia with absent radii (TAR)
D - AD condition, GP1BA mutation, causes large platelets
What types of megakaryocytes are seen in X-linked GATA1 macrothrombocytopenia with dyserythropoiesis? Platelet size? Chromosomal mutation?
- 1) nonlobated or hypolobated
- 2) large plts
- 3) Xp11.23
What is the mutation in TAR? Mode of inheritance?
Large del 1q21; AR
What is the mutation in dyskeratosis congenita?
multiple defective genes in telomere maintenance
Besides the X-linked GATA1 disorder, what disorder can be seen in GATA1 mutations?
Down syndrome, transient abnormal myelopoiesis
What features are shared between TAR and congenital amegakaryocytic thrombocytopenia?
- 1) Isolated thrombocytopenia
- 2) reduced/absent megakaryocytes
- 3) impaired response to THPO
- 4) high plasma THPO
What is the mutation in congenital amegakaryocytic thrombocytopenia (CAMT)?
MPL mutation (THPO receptor on chromosome 1)
Does May-Hegglin anomaly have decreased or increased megakaryocytes?
What physical findings are seen in Fanconi anemia?
- Cafe au lait spots and neurological abnmls
- Hypoplastic thumbs
- Horseshoe kidney
- Duodenal atresia
What is the molecular pathogenesis for the following constitutional BM failure disorders:
1) Fanconi anemia
2) Dyskeratosis congenita
3) Congenital amegakaryocytic thrombocytopenia
- 1) DNA repair pathway (e.g. BRCA1 and BRCA2 mutations)
- 2) Telomere maintenance
- 3) GF receptor mutation (THPO)
What malignancies are Fanconi anemia pts at risk of?
MDS, AML, solid tumors
What is the mode of inheritance of Fanconi anemia?
FANCA is AR (usu 16q24.3), occasionally X-linked recessive - FANCB (Xp22)
How is dyskeratosis congenita similar to Fanconi anemia?
Both have trilineage hematopoietic failure, increased hematologic malignancies, solid tumors
How is dyskeratosis congenita different from Fanconi anemia?
Later onset (adolescence or early childhood), mucocutaneous abnormalities (skin hyperpigmentation, nail dystrophy, mucosa leukoplakia)
Mutations involved in dyskeratosis congenita?
Heterogeneous syndrome, lots mutations, can be AR, AD, X-linked recessive; all genes coding for proteins or untranslated RNA associating with telomerase complex (DKC1, TERC, TERT, etc.)
What abnormalities are seen in Diamond-Blackfan anemia?
1) isolated and sustained red cell aplasia, 2) short stature, 3) craniofacial and thumb abnormalities, 4) malformations
When does Diamond-Blackfan anemia present? Peripheral smear findings? BM findings? Lab findings?
- At birth or within 1st yr of life
- Macrocytic anemia and low reticulocyte count
- BM has almost complete loss erythroids or scattered rare erythroblasts
- Increased Hb F, i antigen on surface, increased RBC adenosine deaminase
How does Diamond-Blackfan differ from Schwachman -Diamond syndrome?
- Shwachman-Diamond is characterized by short stature, exocrine pancreatic insufficiency, BM dysfunction, skeletal abnormalities (metaphyseal dystostosis, thoracic dystrophy, constochondral thickening)
- *Diamond-Blackfan is only anemia rather than BM dysfunction but also has craniofacial malformations, thumb/upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate
What is the mutation in Shwachman-Diamond syndrome? Mode of inheritance?
SBDS gene on chromosome 7q11; AR
When does acquired sustained RBC aplasia present? Morphologic findings? Likely mechanism?
Adolescence through adulthood; normal morphology and MCV; immune-mediated
When does transient erythroblastopenia of childhood present? What other hematologic findings? Possible causes?
Usually >1yo; neutropenia; possible viral causes (HHV6, parvovirus, Kwasaki)
What constitutional neutropenia syndrome has neurologic impairment and oculocutaneous albinism?
Griscelli syndrome, type 2
Name four disorders that have giant platelets.
- 1) Bernard Soulier
- 2) Alpha granule disorders (Hermansky Pudlak, Chediak-Higashi)
- 3) May-Hegglin
- 4) Type 2B vWD
What syndrome shows swiss cheese-like ceroid inclusions in macrophages and occasionally pulmonary fibrosis and absent radii?
What constitutional neutropenia syndrome has platelet dysfunction and oculocutaneous albinism?
Hermansky-pudlak syndrome, type 2
What is WHIM syndrome?
- Myelokathexis (severe chronic leukopenia and neutropenia)
- *Also get granulocytic right-shift with morphologic abnormalities and degenerative changes
What constitutional neutropenia syndrome has cardiomyopathy and skeletal myopathy?
What constitutional neutropenia syndrome has psychomotor retardation and facial dysmorphism?
What mutation analysis is helpful in severe congenital neutropenia?
ELANE (ELA2) mutation analysis
What BM findings are seen in Shwachman-Diamond syndrome?
Granulocytic hypoplasia with left-shift; variably preserved erythroid and megakaryocytic lineages (~40% have multiple affected lineages); cellularity is variable
Major cause for morbidity in Shwachman-Diamond syndrome?
MDS or AML
When does severe congenital neutropenia and cyclic neutropenia present? How do they present? BM findings?
Infancy; severe infections due to profound neutropenia or agranulocytosis; granulocytic hypoplasia/aplasia with left-shift with occasional binucleated or multinucleated promyelocytes
Most common mode of inheritance in severe congenital neutropenia? Mutation in the Kostmann syndrome cases?
AD; AR, HAX1 mutation encoding anti-apoptotic mitochondrial protein
How is cyclic neutropenia distinguished from severe congenital?
Predictable hematopoietic rebound with myeloid hyperplasia and full maturation
Cause of morbidity in severe congenital neutropenia?
MDS and AML development, esp with CSF3R mutations
What is the abnormality in WHIM syndrome?
- Granulocytic production/maturation intact but mature neutrophils not released from BM (myelokathexis) so neutrophils hypermature with overcondensed nuclei and long thin strands
What is the most common type of congenital dyserythropoietic anemia (CDA)? Morphology? Test of choice?
- Type 2 - multinucleate erythroid precursors (see above); positive acidified serum test
What is the difference btw CDA type 2 and PNH with respect to the ham test (acidified serum test)?
PNH shows lysis in both autologous and heterologous serum; CDA type 2 shows lysis in heterologous serum only
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