Bone marrow failure syndromes Flashcards by Ned Jones

Diamond blackfan anemia clinical features + lab features

Lab =
1) infant with progressive macrocytic anemia + reticulocytopenia
2) high EPO level (ineffective erythropoiesis)
Clinical
- congenital malformations (craniofacial abnormalities, thumb anomalies, cardiac anomalies, hypogonadism, intellectual disability)
- short stature
- predisposition to cancer
- bone marrow lacking RBC precursors

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Diamond blackfan anemia pathophysiology

ribosomopathy (gene mutations affecting ribosome synthesis and processing)
ribosome defects reslts in activation of TP53 pathway, which impairs erythropoiesis

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Diamond blackfan anemia diagnosis

Initial evaluation:
- Measurement of fetal hemoglobin (Hgb F; eg, by Hgb electrophoresis)
- Increased erythrocyte adenosine deaminase (eADA) activity
Confirmatory:
- genetic testing for mutations in genes associated with DBA
- bone marrow biopsy but not done at all centers

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Diagnostic features of diamond blackfan anemia

1) Onset of anemia at age <1 year
2) Macrocytic anemia with no other significant cytopenias
3) Reticulocytopenia
4) Normal marrow cellularity with a paucity of erythroid precursors

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Fanconi anemia mechanism

Defect in DNA repair and oxidative stress

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Fanconi anemia gene mutations

FANCA
FANCC
FANC-G

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Fanconi anemia clinical features

pancytopenia
short stature
microcephaly
cafe au lait spots
hypoplastic thumbs

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Fanconi anemia sequelae

MDS
AML
ALL

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Fanconi anemia diagnosis

chromosomal breakage studies using diepoxybutane (DEB) (CONFIRM), confirmed with genetic testing

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Fanconi anemia treatment

steroids
danazol
transplant w/ low dose TBI conditioning and alkylating agent (cytoxan)

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Dyskeratosis congenita mechanism

telomere maintenance dysfunction

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Dyskeratosis congenita mutation

DKC1 gene mutation
OR TERC gene

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Dyskeratosis congenita inheritance pattern

x linked or autosomal dominant

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Dyskeratosis congenita clinical features

dyskeratotic hair, nails
leukoplakia
reticular rash
skin hypertrophy
ataxia
esophageal strictures
squamous cell carcinoma of head neck, GI, or GU tract
pulmonary fibrosis

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Dyskeratosis congenita treatment

androgens
can be role for GCSF or ESA
transplant curative (ensure donor is not a silent carrier) w/ non-myeloablative conditioning

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GATA2 1) lab features 2) monomac clinical features

monocytopenia
b and natural kill cell lymphocytopenia
mycobacterial infections
HPV leading to multiple warts

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GATA2 treatment

stem cell transplant

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GATA2 sequela

MDS, AML

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Diamond blackfan mutations and inheritance

RPS19 gene (autosomal dominant)
OR
GATA1 (x-linked)

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Diamond blackfan anemia treatment

steroids

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Severe congenital neutropenia pathophys

misfolded neutrophil elastase, leading to neutrophil arrest at promyelocyte phase

Severe congenital neutropenia mutation

ELAN

Severe congenital neutropenia clinical features

*delayed cord separation at birth
recurrent infections

Severe congenital neutropenia treatment

GCSF
transplant

Schwachman-diamond syndrome CBC abnormality

- congenital neutropenia

Schwachman-diamond syndrome gene mutation

SBDS gene

Schwachman-diamond syndrome clinical features

- *neutropenia only - pancreatic insufficiency - skeletal deformities - cognitive dysfunction - Failure to thrive

Schwachman-diamond syndrome treatment

- GCSF - transplant

Congenital amegakaryocytic thrombocytopenia mechanism

reduced megakaryocytes from defective response to TPO

Congenital amegakaryocytic thrombocytopenia gene mutation

TPO receptor gene - CMPL gene

Congenital amegakaryocytic thrombocytopenia treatment

transplant plt transfusions

wiskott aldrich clinical features

thrombocytopenia immunodeficiency eczema GI bleeds

wiskott aldrich treatment

IVIG for infections splenectomy transplant

Germline mutation commonly assocaited with Monosomy 7 MDS in young adult patients

GATA2

General clinical features of inherited bone marrow failure syndromes

typically slow symptom onset + longer history/variably low blood counts + developmental or other organ system abnormalities

Genes associated with Diamond-Blackfan anemia

RPL - 5, 11,19 RPS - 10, 19

Very severe aplastic anemia criteria

ANC <200 *think this is the threshold below which pts are at risk of severe infection and death

Basic aplastic anemia algorithm since 1990s

IF <40 years (and typically matched related donor) → IF rapidly available MRD (only 15-30%), proceed directly Allo-HSCT IF unavailable → immune suppression as bridge to allo-HSCT (process can take 6-8 weeks) IF count recovery and no clonal evolution, wean immunosuppressive therapy and observe IF refractory/relapse/MDS develops, haploidental or Unrelated donor SCT

What is triple IST for aplastic anemia?

Equine ATG + cyclosporine + eltrombopag

Sequelae of bone marrow failure disorders

- all have a high risk of cancer: MDS/AML *Also solid tumors in FA, DC, and SDS - hypersensitivity to radiation and chemo in most as well

Fanconi anemia inheritance

- most autosomal recessive

Pathway fanconi anemia is related to

BRCA2 BRCA2 gene = FANCD1 gene

Subtype of fanconi anemia associated with T-ALL

FANCD1 (Biallelic BRCA2)

sequelae of telomere disorders and dyskeratosis congenita

1000x risk of head/neck cancers - also derm and anorectal

Diamond blackfan anemia and malignancy association

At risk of lower GI + osteosarcoma

SCN bone marrow

neutrophil arrest at promyelocyte stage

Cyclic neutropenia clinical features

- mouth ulcers - interval fevrs

Severe congenital neutropenia treatment

- GCSF can normalize ANC but at a cost (severe osteopenia, splenomegaly, high risk of progression to MDS/AML) *so need transplant *SCT outcomes much better before MDS/AML

congenital amegakaryocytic thrombocytopenia gene mutation

c-MPL (TPO receptor)

Schwachman diamond syndrome genetic associations

- biallelic TP53 mutations - del(7q)