Bone marrow failure Flashcards

Question

Diamond Blackfan Anaemia

Answer 1

Ribosomopathy caused by mutations in ribosomal proteins Most AD with variable penetrance Presentation: Usually < 1.yo Elevated Red cell ADA (can be diagnostic) Elevated HbF Macrocytic anaemia, mild other cytopenias reticulocytopenia BMAT - normocellular but reduced erythroids Molecular - RPS19, Other RPL genes Clinical fx: - half may have no congenital abnormalities - thumb and radius defects - heart defects - increased no-haem cancer risk TREATMENT: Steroids improve anaemia in majority of patients  Supportive care (transfusion) preferred until the age of 12/12 to reduce exposure (growth) and allow for vaccine responses  -40% remain dependent on transfusion  AlloHSCT curative  -best performed in young patients without iron overload  -however need to balance with potential for spontaneous remission 

Answer 2

Ribsosomal biogenesis disorder caused by mutations in SBDS (7q11)  . SBDS crucial role in joining 40S and 60S ribosomal units to form 80S ribosome. 90% biallelic  Autosomal recessive  Others: DNAJC21, ELF1  Haem presentation - variable neutropenia - anaemia or macrocytosis - thrombocytopenia - BMA - hypocellular, leukemia Other clinical features: - GI insufficiency - FAECAL ELASTASE - skeletal deformities - immune/cognitive/endocrine dysfunction Molecular: - close haem f/u and cytogentic surveillance - isochrome 7q and del20q - tp53 commonly mutated TREATMENT: - supportive with oral enzyme replacement, GCSF, transfusion AlloSCT only curative option

Answer 3

Ends of DNA are short or damaged - these ends (telomeres) protect the DNA from damage Pathogenesis : - long TTAGGG repeats at chromosome ends, shorten with each cell division. Many pathways maintain telomere length - Abnormal ageing of BM stem cells through defective telomere maintenance  Genetics  DKC1 --> 40% of cases  -XLR (x linked recessive) -encodes dyskerin  -telomere maintenance, ribosome biogenesis  -associated with early childhood onset, multisystem disease  TERT --> up to 7%  -AD or AR  -enzymatic component of telomerase complex  TERC --> 5%  -AD  -internal RNA template strand  Haem presentation: - BMF --> MDS/AML Clinical presentation: - Triad - nail dystrophy, leucoplakia, abnormal skin pigmentation/rash Organs - pulmonary fibrosis, liver cirrhosis, hepatopulmonary/syndrome Ix: Telomere length testing with telomere flow FISH (Westmead, not rebatable) - reduced length <1st centile in lymphocytes. - peptide nucleic acid probes to telomeres (for  --> flow (analysis by signal strength and subset markers)  TREATMENT - androgens (danazol/oxymetholone) - alloSCT - Poor prognosis with mean survival of 30 years

Answer 4

Transcription factor important for early haematopoiesis  Germline heterozygous mutations --> distinct clinical syndrome  Acquired AA  Haem: Cytopenias presenting with assoc infection - MONOCYTOPENIA PB: monocytes/B cells and NK cells reduced - Hypocellular marrow with meg dysplasia and absent B haematogones - AML 90% risk Cytogenetics: monosomy 7 trisomy 8 (risk MDS to AML) Myeloid NGS: acquired ASXL1 most common GATA2 sequencing Treatment - alloSCT

Answer 5

tumors suppressor gene 7q - Gain of function heterozygous mutations   7q  Suppression of haematopoiesis  Preferential loss of 7q when evolves --> protects from growth restriction but clonal evolution to MDS  Very common cause of monosomy 7 MDS  MIRAGE Syndrome  -Myelodysplasia  -Infections  -Restrictions of Growth  -Adrenal hypoplasia  -Genital Abnormalities  -Enteropathy  SAMD9L  BM failure/cytopenias similar to GATA2  -B/NK deficiency  -progression to MDS with del7q  Plus ataxia (cerebellar dysfunction) Must check NON-HAEM sample for SAMD9/SAMD9L in del7q MDS   -loss of germline abnormality (7q) due to preferential loss   

Answer 6

And new ones SAMD9/SAMD9L (with pre existing organ dysfunction) and TP53 (without pre existing plt disorder or organ dysfunction)!

Answer 7

Located on 5q Encodes a DEAD box RNA helicase Likely to be involved in splicing of pre-mRNAs Role in malignancy and immunity

Answer 8

Myeloid neoplasms associated with germline predisposition include AML, MDS, MPNs and MDS/MPN that arise in individuals with genetic conditions associated with increased risk of myeloid malignancies. Heterogenous group of disease caused by deleterious germline pathogenic variants in genes that affect critical biological pathways. They are divided into categories - those with/without pre existing platelet disorder or organ dysfunction

Answer 9

3-8/million prevalence Impaired differentiation of neutrophils Neuts <0.5 BMAT -> maturation arrest at promyelocyte stage Rx: G-CSF to get neut >1

Answer 10

1. Myeloid neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction - Germline CEBPA - Germline DDX41 - Germline TP53 2. Myeloid neoplasms with germline predisposition and pre-existing platelet disorders - Germline RUNX1 - Germline ETV6 - Germline ANKRD26 3.Myeloid neoplasms with germline predisposition and potential organ dysfunction - Down syndrome - telomere biology disorders - germline GATA2 - Germline SAMD9

Bone marrow failure Flashcards

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