Inherited bone marrow failure syndromes - PowerPoint Presentation

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Inherited bone marrow failure syndromes

Josu de la FuenteDepartments of Paediatrics and HaematologyImperial College London

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25% of paediatric and 10% of young adult patient presenting with aplastic anaemia

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Fanconi Anaemia

Median age of presentation 7 years of ageAutosomal recessive disorderSomatic abnormalitiesBone marrow failureGenomic instability and predisposition to cancer

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Somatic/congenital abnormalities in FA

Abnormality Approximate incidence (%) Skeletal [eg radial ray, congenital hip, vertebal, rib] 71 Skin pigmentation [café au lait, hyper/hypo pigmentation] 64 Short stature 63 Eyes [micropthalmia] 38

Renal and urinary tract 34

Male genital 20

Mental retardation 16

Gastrointestinal [eg anorectal, duodenal atresia] 14

Heart 13 Hearing 11 Central nervous system [eg hydrocephalus] 8 No abnormalities 30

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Chromosomal Fragility Test

Peripheral blood T-lymphocytes are stimulated to divide with a mitogen and then exposed to a DNA cross-linking agent such as diexpoxybutane (DEB) or mitomycin C (MMC).Metaphase spreads of FA cells have increased numbers of chromosomal breaks per cell and an increased fraction of cells with breaks.Somatic mosaicism: normal test in some patients with FA because hemopoietic stem cell has undergone gene correction, and its progeny have repopulated the bone marrow. Skin fibroblasts should be used for the breakage.

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ctb

ctb

mci

ctb

ctg

CHROMOSOMAL ABNORMALITIES

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Complementation Group

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FA and cancer:

Observed/expected ratio of approximately 800 for AML and 50 for all cancersRelative risk is in the thousands for esophageal and vulvar cancers, and in the hundreds for HNSCC and liver tumoursProbability of a solid tumour is 75% by age 45 years, and of leukaemia 30% by age 30 yearsFANCD1/BRCA2 and FANCN have very high rates of severe birth defects and early childhood onset brain tumors, Wilms tumour, and AML.

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Management:FBC and blood film every 3 to 4 months.

Annual bone marrow aspirate and biopsies including cytogenetics.Solid tumor surveillance by dentists, head and neck squamous cell carcinoma and gynecologists.Impact on HNSCC and gynecologic cancers of HPV vaccine for human papilloma virus is awaited.Androgens: oxymetholoneStem Cell Transplantation: special conditioning regimens due to chromosomal fragility

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Diamond Blackfan Anaemia

Hypoplastic anaemia in infancy (lack of erythroid precursors in BM)30% short staturePhysical abnormalities:Triphalangeal thumb, flattened thenar muscles, absent thumbCleft palate and other midline abnormalities

Cardiac abnormalities 15-20%

Renal abnormalities 15-20%

Progression to other cytopaenias/complete aplasia

Cancer risk:

5% from 0.1% bakground < 30 years of ageMedian age 15 years from 68 years in normal populationsMDS, AML, osteogenic sarcomas.

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steroid dependent

steroids withdrawn

spontaneous remission

never responded

response lost

transfusion independent

transfusion dependent

n=40 (60%)

n=27 (40%)

Diamond Blackfan Anaemia:

summary of treatment status

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Chronic transfusion programme:

Pre-transfusion Hb: 8-10 g/dL depending growth and exercise toleranceChelation therapy: desferrioxaminedeferasiroxStem Cell Transplantation:Achieves resolution anaemia and need for regular blood transfusions causing end-organ damage due to iron accumulation

May reduce the risk of cytopaenias and risk of AML/MDS

May increase the risk of solid tumours

Does not resolve other systemic features of the condition

Cancer advice:

Not to smokeDiet with fibreDo not use growth hormoneHPV vaccine

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Median age at diagnosis is 15 yearsDiagnostic triad frequently absent:

Lacey reticulated pigmentationDysplastic nailsOral leukoplakiaDCR includes those with at least one triad feature plus at least two other somatic features.Early childhood variants of DC:Hoyeraal-Hreidarsson syndrome: intrauterine growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency, and bone marrow failure

Revesz syndrome: similar features plus exudative retinopathy

Dyskeratosis Congenita

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Incidence of marrow failure is 94% by age 40 yearsPulmonary fibrosis

Frequency of malignancy:9% to 10%majority are carcinomas, particularly head and neck and oesophageal in 60% of the patients, and colon and anus in 15%.AML and myelodisplasiaUnlike FA, where the frequency of AML and solid tumors is equivalent, solid tumours are much more frequent in DC.Cumulative incidence by age 50 years is 35% for all malignancies, substantially lower than in FA, but still striking.

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Dyskerin

~57kDa

TERT

~130kDa

NHP2

~22kDa

NOP10

~10kDa

TERC

451b

GAR1

~25kDa

Putative associations between dyskerin, TERC and TERT in the telomerase complex

Mutated in

X-linked DC

Mutated in AD DC and aplastic anaemia

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Telomeres and Telomerase

Tandem repeats of the TTAGGG

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Shwachman-Diamond Syndrome

Autosomal-recessive disorder, primarily diagnosed in childhood:Malabsorption with excessive fatty stools due to pancreatic exocrine insufficiencyFailure to thriveShort statureMetaphyseal dysostosis particularly at the hips and femurs in 50%Some patients have learning disabilities

Haematology:

Neutropenia is usually identified during the general evaluation.

Other cytopenias and macrocytosis may be observed

Many patients evolve to aplastic anemia, MDS, or leukemia.

Median age for leukaemia is 18 years / Age-dependent cumulative probability of leukemia is greater than 70%. No solid tumors.

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Diagnosis:serum

trypsinogen (which may improve with age)isoamylase (which fails to increase after age 3 years)elastase in stoolsdetection of a fatty pancreas by USS, CT or MRIneutropenia < 1.5 x 109

/L on more than one occasion

Patients often have bone marrow cytogenetic clones:

particularly involving chromosome 7:

monosomy

7, der(7), and i(7q)], as well as del(20q).No patients with i(7q) were reported to develop AMLAlthough 50% clones associated with dysmyelopoietic or hypoplastic bone marrow morphologySignificant of clones not known

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More than 95% of patients who meet the diagnostic criteria for SDS have mutations in one gene: SBDS.

Most mutations are due to gene conversion between the SBDS gene and an adjacent pseudogene.There are two common alleles: null allele and hypomorphic:some SBDS protein is apparently required, because no patients are homozygous for the null alleleSimilar to the RPS genes in DBA, SBDS also has a function in ribosome formation: involving the 60s subunit.The reason for neutropenia or bone marrow failure in patients with

SBDS

mutations remains unclear.

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Treatment of malabsorption:administration of pancreatic enzyme supplements with food

addition of fat soluble vitamins (A, D, E, K)Pancreatic function often improves with age, and fewer or no supplements may be needed by adult patients.Treatment of neutropenia:Infrequently of clinical significanceUsually improves on low doses of G-CSFThere is no evidence that is associated with an increase in the already high baseline risk of AML.

Bone marrow function:

Does not improve with age

Clonal cytogenetics, MDS, and leukemia may develop

Patients should have frequent blood counts and annual bone marrow

SCT has been used successfully in many patients with SDSthere is increased cardiac toxicity from cyclophosphamide.

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Severe Congenital Neutropaenia

Group of disorders:early onset neutropenia (< 0.5 x 109/L)pyogenic infectionsmarrow maturation arrest in granulopoiesisDiagnosis is usually made in infancy.Inheritance:

Autosomal recessive in the family first described by Kostmann

Most cases are sporadic or autosomal dominant

No characteristic physical abnormalities

Cyclic neutropenia needs to be excluded, ideally by obtaining blood counts twice weekly for 6 weeks, since the usual cycle is approximately 21 days.

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Choi, Society of Hemopathology Case August 2004

Other causes of neutropenia should also be excluded:

Immune neutropaenia of childhood: positive anti-neutrophil antibodies

Hypersplenism

MDS

Leukaemia

Bone marrow marrow examination:Promyelocyte or early myeloid arrestRule out early cytogenetic changes for a clonal disorder

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Genetics:

Most patients dominant mutation in the gene for neutrophil elastase, ELA22% have a mutation in GFI1Small proportion have X-linked disease due to mutations in WASA few families, including original Kostmann, homozygous mutations in HAX1.33

Patients with cyclic neutropenia also have mutations in

ELA2.

Cyclic and SCN mutations are generally separated at the amino- and carboxy-terminal parts of the gene.

The function of the normal SCN genes may be to prevent apoptosis of myeloid precursor cells.Somatic mutations in G-CSFR:Several patients with SCN (particularly those with AML)Prospective study has not been done to determine whether this is predictive of leukaemic transformation

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Treatment of neutropenia:G-CSF, to which most respond with improved neutrophil counts

Aim: raise count > 1.5 x 109/L usually using 5 to 10 μg/kg/day or every other dayRisk of G-CSF and leukaemia:3 patients with SCN who developed AML in the pre–G-CSF era suggesting that SCN is a pre-leukaemic disorder

Following more than 20 years of use of G-CSF it is clear that MDS/AML is a part of the syndrome.

Analysis of 374 patients in the SCNIR:

Cumulative incidence of MDS/AML increased with time on treatment, reaching 21% after 10 years, while death from sepsis was 8%.

Patients who had “healthier” stem cells required lower doses of G-CSF (below the median of 8

μg/kg/day) in order to attain the target neutrophil count, and had a cumulative incidence of MDS/AML of 11%.Patients whose stem cells did not respond to lower doses and who despite higher G-CSF doses (above the median) still did not achieve an adequate neutrophil count: cumulative incidence of MDS/AML of 40%.Unresponsive patients should be considered for SCT, particularly if matched sibling available.No solid tumours were reported.

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Congenital Amegakaryocytic Thrombocytopaenia

No characteristic physical appearance, except for bruises due to thrombocytopeniaUsually presents in infancy with thrombocytopenia, which often progresses to aplastic anaemia and/or AML.Since mild thrombocytopenia may be missed:Some patients are only diagnosed retrospectivelyConsider in any young patient with non-immune thrombocytopenia, or pancytopenia, particularly with macrocitosis and/or increased Hb F

Cumulative incidence:

Aplastic anaemia: 91% by age 13 years.

AML: 55% by age 17 years.

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Projected median age:

Aplastic anaemia: 5 yearsAML: 17 years No solid tumours have been reported.

Sola, Journal of Perinatology 2004

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Genetics:Autosomal recessive.

Mutations in c-mpl: gene for the receptor for thrombopoietin, the hematopoietic growth factor that stimulates megakaryopoiesis.Genotype/phenotype correlation:Null mutations result in severe early thrombocytopenia and rapid progression to pancytopeniaMissense mutations have some improvement in platelet counts early in childhood and delayed evolution to aplastic anaemiaNumbers too small to now whether risk of AA and AML differsTreatment:

SCT although they may respond to androgens.

No excess toxicity as FA and DC.

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Thrombocytopenia Absent Radii

Suspected at birth in a child with absent radii but thumbs present, albeit often malformed (FA, thumbs are absent if radii are absent) and low plateletsTransient leukaemoid reaction is also common (ascribed to cows’ milk allergy).Survival curve reaches a plateau of 78% at age 5 years.Additional somatic anomalies:short or absent ulnaeabsent humeri

dislocated hips

abnormal knees

cardiac defects

Risk of AML and possibly solid tumours, but not aplastic anaemia

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Gene: microdeletion involving 11 genes on chromosome 1q21.1 has been found to be necessary but not sufficient

10 to 20% of infants with TAR require transfusionsIn most cases the platelet count starts to rise by 1 year of ageMay reach a level at which orthopedic surgery can be performed without platelet cover, although it does not usually become normalSCT is a very rare requirement