Inherited bone marrow Failure Syndromes (IBMFs) Flashcards
(24 cards)
What are Bone marrow failure syndromes?
Bone marrow failure syndromes (BMFs) are a group of heterogeneous disorders characterized by one- or two-lineage cytopenia or pancytopenia caused by inefficient hematopoiesis in the bone marrow
What are the two subgroups of pediatric BMFs? What is their prevalence?
- Acquired BMFs (ABMFs), ABMFs account for 80% of pediatric MFs
- Inherited BMFs (IBMFs). Accounts for 20% of pediatric MFs
Q Define IBMFs
IBMFs are a rare heterogeneous group of hereditary disorders characterized by progressive single-lineage or multi-lineage cytopenia and a high risk for myelodysplasia (MDS) and acute myeloid leukemia (AML).
What is the common pathophysiology of IBMFs?
Which malignancies are related to BMF’s?
- diverse mutant genes.
- Many of these genes encode proteins that are involved in cellular housekeeping pathways, and
- perturbing these pathways can cause cellular senescence (premature aging and arrest of cell division) and apoptosis as well as predispose cells to malignant transformation eg. AML (mostly) and MDS
The inherited disorders are characterized by
- bone marrow ( BM) failure, usually in association
- with one or more somatic abnormalities
The precise incidence/prevalence of these remains unclear but, collectively, they represent approximately 10–20% of patients presenting with Aplastic Anaemia (AA).
What are the two syndromes that are frequently associated with generalized BM failure (involving all the three cell lines)?
What makes their diagnosis/management challenging?
Fanconi anaemia(FA) and
dyskeratosis congenita (DC).
FA and DC patients can sometimes present with AA alone as their initial manifestation and can thus pose a diagnostic/management challenge
What is the Physical stigmata of inherited marrow failure syndromes?
Abnormal skin pigmentation
Short stature
Renal, cardiac, and gastrointestinal (GI) abnormalities
Microcephaly
Microphthalmos
Hypogonadism
Skeletal anomalies
The oral pharynx, hands, and nail beds should be carefully examined for clues of inherited bone marrow-failure syndromes
Q Tabulate 5 examples each of inherited bone marrow failure syndromes causing pancytopenia and single cytopenia
Pancytopenia
- Fanconi anaemia (FA)
- Dyskeratosis congenita (DC)
- Shwachman–Diamond syndrome (SDS)
- Reticular dysgenesis
- Pearson syndrome (PS)
- Familial aplastic anaemia (autosomal and X-linked forms)
- Myelodysplasia
- Non-haematological syndromes
(Down, Dubowitz syndromes)
Single cytopenia (usually)
1. Anaemia (Diamond–Blackfan anaemia, DBA)
2. Neutropenia (severe congenital neutropenia, SCN, including Kostmann syndrome)
3. Thrombocytopenia (congenital amegakaryocytic thrombocytopenia CAMT, amegakaryocytic thrombocytopenia with absent radii, TAR)
Discus FA and its abnormalities
First described by Fanconi in 1927.
an autosomal recessive disorder in which there is progressive BM failure and an increased predisposition to malignancy, especially acute myeloid leukaemia.
May have one or more somatic abnormalities including:
* skin (café-au-lait spots),
* skeletal (absent thumbs, radial hypoplasia (underdevelopment or partial/complete absence of the radius bone), scoliosis, short stature),
* genitourinary (underdeveloped gonads, horseshoe kidneys),
* GI, cardiac and neurological anomalies (mental retardation)
* Hearing defect
- approximately one-third of patients having no somatic abnormalities.
What is the incidence of symptoms (age of onset)?
What are the clinical features of FA?
What is the main cause of death in patients with FA?
What is the mean survival time?
Malignancies it can lead to?
The cumulative incidence of BM failure by the age of 40 years is 90%.
At birth the blood count is usually normal. Pancytopenia develops insidiously and presents in most cases between the ages of 5 and 10 years (median age 7 years).
However, in some cases the pancytopenia develops in adolescence or even in adult life.
BM failure leading to fatal haemorrhage or infection is the main cause of death in FA patients.
The median survival time was 24 years.
FA is associated with an increased risk of leukaemia and other malignancies, usually AML M4 and M5
In some cases, leukaemia may be the initial event leading to the diagnosis of FA.
Discuss the molecular diagnostic features
Cells from FA patients show an abnormally high frequency of spontaneous chromosomal breakage and hypersensitivity to the clastogenic (Chromosome breaking) effect of DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC).
A laboratory test is available for this, comparing response with normal control subjects after exposure to low concentrations of DEB or MMC (‘DEB/MMC stress) test.
There is considerable genetic heterogeneity in FA, with evidence for eight complementation groups (FA-A, FA-B, FA-C, FA-D1, FA-D2, FA-E, FA-F and FA-G),
Discuss the treatment of FA
This includes administrating androgens (oxymetholone) and corticosteroids(prednisolone).
Androgens improve hematopoiesis by at least 2 mechanisms.
First, androgens increase the red blood cell mass by stimulating the production of erythroid progenitors in the bone marrow either by increasing erythropoietin (EPO) production in the kidneys or by directly activating the EPO receptor on progenitor cells.
Second, androgens also increase telomerase (TERT) gene expression in hematopoietic cells.
Oxymetholone can produce useful, trilineage responses >50% of patients, however the majority will become refractory.
Oxymetholone is associated with side-effects,
including liver dysfunction and increased risk of hepatic tumours.
It is a very good holding treatment until more definitive treatment can be planned using haemopoietic SCT, which has now become the treatment of choice
What is DC and its PATHOGENESIS?
What is the diagnostic physical triad of DC?
PATHOGENESIS
X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized.
It is therefore now acknowledged that DC is a very heterogeneous disorder, both clinically and genetically.
Dyskeratosis congenita is characterized by the diagnostic physical triad of:
* dysplastic nails
* lacy reticular pigmentation of the upper torso and
* oral leukoplakia
Discuss the Molecular diagnostic features of DC
In general there is no significant difference in chromosomal breakage between DC and normal lymphocytes with or without the use of bleomycin, DEB, MMC and γ- irradiation.
This observation enables DC patients to be distinguished from FA.
DC, like FA, may thus be regarded as a chromosomal instability disorder but with a predisposition principally to chromosomal rearrangements rather than the gaps and breaks seen in FA.
Discuss the treatment of DC
oxymetholone produces improvement in (> 50%) patients for a variable period of time.
May respond to granulocyte–macrophage colony-stimulating factor (GM-CSF), G-CSF and erythropoietin.
The main treatment for severe BM failure, is allogeneic SCT, the results of conventional transplants have been less successful than in FA.
The presence of pulmonary disease in a significant proportion of DC patients perhaps now explains the high incidence of fatal pulmonary complications in the setting of SCT.
It also highlights the need to avoid agents (such as busulphan and radiotherapy) that are associated with pulmonary toxicity.
Perhaps the best candidates for SCT are patients with no pre-existing pulmonary disease and who have sibling donors.
DC is theoretically a good candidate for haemopoietic gene therapy
What are the clinical features of Shwachman–Diamond syndrome (SDC)?
Clinical features
Is an autosomal recessive disorder characterized by
exocrine pancreatic insufficiency ,
bone marrow dysfunction and
other somatic abnormalities (particularly involving the skeletal system).
Signs of pancreatic insufficiency (malabsorption, failure to thrive) are apparent early in infancy
Other common somatic abnormalities include
short stature (~70%),
protuberant abdomen and an ichthyotic skin rash (~60%).
Other abnormalities include hepatomegaly, rib/thoracic cage abnormalities, hypertelorism, syndactyly, cleft palate, dental dysplasia, ptosis and skin pigmentation.
The spectrum of haematological abnormalities includes other cytopenias (approximately 20% have pancytopenia), myelodysplasia and leukaemic transformation (~25%).
The age at which leukaemia develops varies widely from 1 to 43 years. Acute myeloid leukaemia is the commonest category
Discuss the treatment of SDC
The malabsorption in SDS responds to treatment with oral pancreatic enzymes.
For those with neutropenia, G-CSF may produce an improvement in the neutrophil count.
Transfusions and use of oxymetholone
The main causes of death are infection or bleeding.
Analysis of SDS patients has showed increased incidence of myelodysplasia and transformation to acute myeloid leukaemia (~15–25%).
SDS is regarded as a disorder with high propensity to develop both AA and leukaemic transformation, particularly acute myeloid leukaemia with erythroid differentiation (AMLM6).
Single lineage failures: Diamond–Blackfan anaemia
Clinical features
Red cell aplasia was first reported in 1936 by Josephs. In 1938, Diamond reported on four children with hypoplastic anaemia, and this has now come to be recognized as Diamond–Blackfan anaemia (DBA) or congenital pure red cell aplasia.
Based on the typical selective deficiency in red cell precursors, many researchers believed that DBA is due to an intrinsic problem with erythroid proliferation/ differentiation.
The subsequent finding of RPS19 mutations in 10 out of 40 unrelated DBA patients provided good evidence for the primary role of this gene in the pathogenesis of DBA in approximately 25% of DBA cases.
Most of the familial cases displayed autosomal dominant pattern of inheritance.
DBA usually presents in early infancy, with symptoms of anaemia such as pallor or failure to thrive.
The hallmark of classical DBA is
a selective decrease in erythroid precursors and normochromic macrocytic anaemia associated with
a variable number of somatic abnormalities such as craniofacial, thumb, cardiac and urogenital malformations
Somatic anomalies, such as high-arched palate, cleft lip, hypertelorism and flat nasal bridge, upper limb and hand (flat thenar eminence, triphalangeal thumb), genitourinary and cardiac.
MDS and AML have been reported in a few patients with DBA, suggesting an increased predisposition to haematological malignancies.
There are also cases that have evolved into AA; neutropenia and thrombocytopenia are relatively common after the first decade.
Diagnosis, treatment of DBA
Hitherto the diagnostic criteria for DBA have been
(i) normochromic, usually macrocytic, but occasionally normocytic anaemia developing in early childhood;
(ii) reticulocytopenia;
(iii) normocellular BM with selective deficiency of erythroid precursors (erythroblasts < 5%);
(iv) normal or slightly decreased leucocyte counts; and
(v) normal or often increased platelet counts.
The annual incidence of DBA is ~5 per million live births. The median age at presentation of 8 weeks and 93% of patients presented in the first year of life.
Majority responds to steroids, and some become transfusion dependent.
Splenectomy may be indicated in the event of an increased transfusion requirement secondary to hypersplenism.
The first line of treatment for DBA remains corticosteroids. Once a maximal Hb response has been achieved, the dose of prednisolone should be tapered slowly until the patient is on the lowest dose possible on an alternate-day regimen.
For those patients who fail to respond or become refractory to steroids, blood transfusion is the mainstay of treatment.
Splenectomy may be indicated in the event of an increased transfusion requirement secondary to hypersplenism.
For patients who are transfusion dependent and who have a compatible sibling donor, haemopoietic SCT may be appropriate and is potentially curative.
Congenital and cyclical neutropenias
Congenital neutropenia is a heterogeneous disorder. It includes Kostmann’s syndrome, which was first described in 1954.
Originally described by Kostmann as an autosomal recessive disorder, other congenital neutropenia subtypes (both sporadic and autosomal dominant) have been included subsequently in this category.
The neutropenia is usually recognized at birth and the neutrophil count is often < 0.2 × 109/L.
The Hb and platelet count are usually normal and the bone marrow shows a ‘promyelocyte maturation arrest’ with abundant promyelocytes but with a selective reduction in myelocytes, metamyelocytes and neutrophils.
The neutropenias are associated with severe infections and early death. No patient has developed AA but myeloid leukaemias (~10%) can occur.
G-CSF can be used to treat and SCT may be appropriate and curative.Cyclical neutropenia is characterized by a neutrophil count that usually reaches a nadir (lowest point) with a 21-day periodicity.
Around the nadir, patients may develop fever and mouth ulcers. In cyclical neutropenia, the pattern of inheritance is usually autosomal dominant.
Studies identified mutations in the gene encoding neutrophil elastase (ELA2).
Neutrophil elastase is a serine protease that is synthesized predominantly at the promyelocytic stage and can be expected to be important in neutrophil development.
Discuss Thrombocytopenia with absent radii
Thrombocytopenia with absent radii (TAR) is an autosomal recessive disorder characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia.
Babies with TAR often have haemorrhagic manifestations at birth when the diagnosis is usually made, owing to the characteristic physical appearance combined with thrombocytopenia.
Additional skeletal (absent ulnae, absent humeri, clinodactyly) and other somatic (microcephaly, hypertelorism, strabismus, heart defects) abnormalities may be seen in some patients.
The platelet count is usually below 50 × 109/L. The leucocyte count can be normal or raised, sometimes up to 100 × 109/L (‘leukaemoid reaction’)
BM cellularity is normal and myeloid and erythroid lineages are normal or increased. Megakaryocytes are absent or decreased.
Most patients bleed in infancy and then improve after the first year. The mainstay of management is prophylactic and therapeutic use of platelet transfusions.
TAR patients have a very good prognosis after infancy. There have been no reports of AA or leukaemia.
The pathophysiology of TAR is unknown.
Thrombopoietin levels are usually elevated and thrombopoietin receptor expression on the surface of TAR platelets is normal.
Therefore, defective megakaryocytopoiesis/thrombocytopoiesis does not appear to be caused by a defect in thrombopoietin production.
There is some evidence that it may be due to a lack of response to thrombopoietin in the signal transduction pathway of the thrombopoietin receptor (c-mpl).
Discuss Congenital amegakaryocytic thrombocytopenia (CAMT)
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder that usually presents in infancy and is characterized by isolated thrombocytopenia and reduction/absence of megakaryocytes in the bone marrow, usually with no somatic abnormalities.
It is genetically heterogeneous with autosomal recessive and X-linked subtypes.
Approximately 50% of patients will develop AA usually by the age of 5 years.
For patients with severe thrombocytopenia or AA, the treatment of choice is SCT if a compatible donor is available.
Q features of marrow failure
- Anemia: breathlessness, easy fatiguabulity
- Neutropenia: frequent infections
- Thrombocytopenia: bleeding, easy bruising, epistaxis, Petechiae
Q Mention one word which describes a reduction in all cell lines
Pancytopenia
