Week 2 Lecture 4 - Cytopenia and Bone Marrow Failure Syndromes

Question 1

Pancytopenia

Answer 1

May manifest with symptoms/clinical signs related to anaemia, leukopenia, thrombocytopenia
May be asymptomatic/diagnosed incidentally
Can be an indication of an underlying disease
Commonly reflects trilineage hypoplasia in the bone marrow (= impaired production) but can reflect peripheral destruction or a combination of both

Question 2

Trilineage Hypoplasia (Aplastic Anaemia)

Answer 2

Deceased presence of 3 haematopoietic cell lines
- erythroid
- myeloid
- megakaryocytic
BM morphology
- <25% cellularity with consideration of age & biopsy site
- commonly haematopoietic cells replaced by adipocytes
- may be also be replaced by: fibrous tissue, haematopoietic neoplastic cells, metastasised neoplastic cells

Question 3

Inherited Bone Marrow Failure Syndromes

Answer 3

Inherited bone marrow failure syndromes
(IBMFS) are a group of disorders that result in:
- decreased bone marrow cellularity
- decreased cellularity in the peripheral blood
Include:
- Diamond-Blackfan anaemia
- Schwachman-Diamond syndrome
- Fanconi anaemia
- Severe congenital neutropenia
- Congenital amegakaryocytic thrombocytopenia

Question 4

Diamond-Blackfan Anaemia

Answer 4

Autosomal dominant trait
~25% have mutation in RPS19 located on chromosome 19q13.2
In total 15 genes shown to have result in DBA
These mutations prevent the assembly of ribosomal proteins => ‘ribosomopathy’
Manifests during infancy
Clinical consequences
- haematological abnormalities
- physical abnormalities
- neoplasia

Question 5

Diamond-Blackfan Anaemia - Haematological Findings

Answer 5

PB:
- anaemia (commonly)
- ± macrocytic RBC
- thrombocytopenia - thrombocytosis
BM:
- erythroid hypoplasia => trilineage hypoplasia
- trilineage dysplasia
- megakaryocytic hyperplasia
- fibrosis

Question 6

Schwachman-Diamond syndrome (SDS)

Answer 6

Autosomal recessive disorder
Mutation in SBDS gene on chromosome 7q11.21
Clinical manifestation shortly after birth
- recurrent infections
- pancreatic exocrine insufficiency
- skeletal abnormalities
Clinical consequences
- haematological abnormalities
- physical abnormalities

Question 7

Schwachman-Diamond syndrome (SDS) - Haematological Findings

Answer 7

PB:
- neutropenia (~100%)
- anaemia (~66%)
- thrombocytopenia (~25%)
BM:
- myelodysplasia (~33%)
- left shifted granulopoiesis

Question 8

Fanconi Anaemia

Answer 8

Pathogenic variants in at least 20 genes are known to cause FA in humans
Many mutations documented
Clinical consequences:
- haematological abnormalities
- physical abnormalities
- neoplasia

Question 9

Fanconi Anaemia - Haematological Findings

Answer 9

PB:
- cytopenia (70% by 7 y.o., ‘all’ by 40 y.o.)
- RBC; anisocytosis, poikilocytosis including dacrocytes, basophilic stippling
BM:
- trilineage hypoplasia
- dyserythropoiesis
- reactive mastocytosis

Question 10

Severe Congenital Neutropenia (SCN)

Answer 10

Broad term that encompasses several disorders; all => neutropenia
Present early in infancy with severe infections
>50% due to mutations of ELANE gene, encoding for neutrophil elastase
Less frequent causes of SCN include pathogenic variants in GFI1, WASP, G6PC3, VPS45, JAG1, &TCRG1

Question 11

Severe Congenital Neutropenia - Haematological Findings

Answer 11

PB:
- severe, constant neutropenia <0.5 x109/L
BM:
- ↓ myeloid precursors
- ↓ M:E
- myeloid maturation arrest

Question 12

Haematological Neoplasia with IBMFS - Fanconi Anaemia

Answer 12

Have increased risk of hematologic malignancies, head and neck squamous cell carcinoma (HNSCC), gynecologic cancers, and other solid tumors.
The most frequent hematological malignancies are MDS and AML
The cumulative incidence of AML at 40 years is 15%-20%
The cumulative incidence of MDS at 50 years is 40%

Question 13

Haematological Neoplasia with IBMFS - Diamond-Blackfan Anaemia

Answer 13

Associated with elevated risk of MDS, AML, colon cancer, osteosarcoma, and female genital cancers

Question 14

Haematological Neoplasia with IBMFS - Severe Congenital Neutropenia

Answer 14

Cumulative incidence of MDS/AML is estimated at 11% at 20 years of age and at 22% after 15 years on G-CSF treatment
Although it is clearly demonstrated that G-CSF dramatically improved survival of SCN patients, it is also likely that G-CSF itself affects clonal evolution

Question 15

Haematological Neoplasia with IBMFS - Schwachman-Diamond Syndrome

Answer 15

MDS and/or AML has been reported
Cumulative risk of MDS/leukaemia was 36% at 30 years of age

Question 16

Aplastic Anaemia

Answer 16

Defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis
Diagnosis requires at least two of the following:
- [Hb] <100 g/l, [platelet] <50 x109/l, [neutrophil] <1.5x109/l
The majority of cases are idiopathic

Question 17

Clonal Haematopoiesis

Answer 17

HSCs have the capacity for self-renewal for the lifetime of an individual, consequently mutations arising in HSCs will persist for the lifetime of that individual
If any of these mutations is capable of providing a selective advantage to the HSC in which it arises then clonal expansions results

Question 18

Clonal Haematopoiesis of Indeterminate Potential (CHIP)

Answer 18

CHIP is defined by the presence of a neoplasm-associated somatic mutation in the blood or bone marrow of persons without a known hematologic neoplasm
Used to distinguish the presence of these mutations in non-malignant settings from malignant clonal haematopoiesis
The most common mutations in CHIP are:
- loss-of-function alleles in DNMT3A & TET2
- both encode enzymes involved in DNA methylation
These mutations are found nearly always in circulating granulocytes, monocytes, & NK cells

Question 19

CHIP and Haematopoietic Neoplasia

Answer 19

CHIP predisposes to neoplasia
Commonly myeloid phenotype
Usually results from acquisition of a stronger driver mutation on a background CHIP clone
After stem cell transplantation donor CHIP can contribute to cytopenias, and may also result in donor-derived leukemia
Similarly, after autologous hematopoietic cell transplant clonal haematopoiesis is associated with adverse outcomes

Question 20

Inherited Thrombocytopenias

Answer 20

These represent a group of inherited bone marrow disorders affecting platelet production
Typically:
- platelet concentration is decreased
- platelet size (volume) may be affected
- platelet function is often normal
Several inherited disorders that result in decreased [platelet] have been reported including:
- congenital amegakaryocytic thrombocytopenia
- thrombocytopenia with absent radii syndrome
- radioulnar synostosis with amegakaryocytic thrombocytopenia
- X-linked thrombocytopenia with dyserythropoiesis

Question 21

Congenital Amegakaryocytic Thrombocytopenia

Answer 21

Characterised by severe thrombocytopenia and an almost complete absence of megakaryocytes in the bone marrow
Typically presents within the first month of life with bleeding disorder
The underlying defect causing CAMT is a mutation in the MPL gene causing abnormal expression or function of the thrombopoietin (TPO) receptor
Affected individuals have severe thrombocytopenia with median platelet levels of 20 × 10^9/L
A bone marrow that has normal cellularity but significantly reduced or absent megakaryocytes is suggestive of CAMT
Plasma TPO levels are uniformly elevated in CAMT patients

Question 22

Thrombocytopenia with Absent Radii Syndrome (TAR)

Answer 22

Presents with thrombocytopenia in association with bilateral absent radii & frequently additional congenital abnormalities
TAR is related to an abnormal response of megakaryocytes to TPO
Caused by a microdeletion of 11 genes on chromosome 1q21.1
Diagnosis made by observing severe thrombocytopenia at birth, associated with bilateral radial aplasia and occasionally other skeletal abnormalities in the arms but not in the hands and fingers
Thrombocytopenia can fluctuate from 10-100 × 10^9/L
Accompanied by increased concentrations of plasma TPO

Question 23

Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia

Answer 23

Patients present similarly to congenital amegakaryocytic thrombocytopenia, with early neonatal thrombocytopenia bleeding that eventually progresses to pancytopenia
Mutation in the homeobox gene HOXA11 has been implicated

Question 24

X-linked Thrombocytopenia with Dyserythropoiesis

Answer 24

A group of X-linked disorders characterised by thrombocytopenia associated with RBC defects
Linked to mutations in the GATA1 gene located on Xp11–12
GATA1 encoding GATA-1 protein is an erythroid & megakaryocyte specific transcription factor required for the development of these two lines of haematopoietic cells
Clinically, patients typically have significant bleeding and bruising that can be spontaneous or after a haemostatic challenge
The bone marrow is typically hypercellular with dysplasia in both erythroid and myeloid lines
The diagnosis should be suspected when thrombocytopenia is accompanied by anaemia

Question 25

How to Distinguish X-linked Thrombocytopenia with Dyserythropoiesis from Wiskott-Aldrich Syndrome

Answer 25

X-linked has normal-large sized platelets whereas Wiskott has small platelets